Biomarkers and treatment methods for follicular lymphoma

Abstract

Provided herein are methods and kits that use specific biomarkers to identify subtypes of follicular lymphoma, selectively treat subtypes of follicular lymphoma (FL), identify subjects likely to be responsive to FL treatment, and predict the responsiveness of subjects to FL treatment. TIFF2026529040000042.tif122150

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 507,966, filed on 13 June 2023, the contents of which this patent application are incorporated herein by reference in their entirety.

[0002] Provided herein are methods and kits that use specific biomarkers to identify subtypes of follicular lymphoma, selectively treat subtypes of follicular lymphoma (FL), identify subjects likely to be responsive to FL treatment, and predict the responsiveness of subjects to FL treatment. [Background technology]

[0003] Follicular lymphoma (FL) is considered an indolent lymphoma, but approximately 20% of patients, particularly those with early relapses, experience adverse outcomes (Non-Patent Literature 1). This heterogeneity in the prognosis of FL patients is only partially addressed by indicators used in routine clinical practice and based on classical clinical and biological parameters, such as the FL-International Prognostic Index (FLIPI), FLIPI-2, or PRIMA-PI (Non-Patent Literature 2). To date, efforts to identify prognostic factors from the biological characteristics of FL tumors have not been accurately translated into routine clinical practice.

[0004] The prognostic significance of the tumor microenvironment (TME) has long been inferred through gene expression signature (GES) and immunohistochemistry (IHC) studies, but there is no consensus on which GES or IHC study is preferable (Non-Patent Documents 3, 4, 5, 6, and 7). In fact, the prognostic value of TME markers appears to be treatment regimen-dependent and may have been altered by the widespread use of immunochemotherapy (Non-Patent Documents 8 and 4).

[0005] Molecular risk prediction models based on genomic alterations and GES have been developed, including the m7-Follicular Lymphoma International Prognostic Index (m7-FLIPI) (Non-Patent Literature 9) and a predictor based on the expression of 23 genes (Non-Patent Literature 10). The latter model is somewhat associated with putative "Cellular Origin" (COO), particularly a GES named ICA13, which resembles the dark zone of germinal centers and was associated with poor prognosis. Similarly, another study showed that GES in FL tumors with high FOXP1 expression was enriched in both the dark zone-associated gene set and the activated B cell (ABC) gene set (Non-Patent Literature 11). Some degree of interoperability between these models was suggested by a shared, controlled expression network (Non-Patent Literature 12). However, the results of these models are inconsistent, and their biological significance and impact on treatment decisions in individual FL patients remain unclear.

[0006] COO, defined by genetic profiling, allows for the molecular classification of diffuse large B-cell lymphoma (DLBCL) between prognostically advantageous germinal center (GC) subtypes and unfavorable ABC subtypes (Non-Patent Literature 13, 14, and 15). However, similar subcategorization has long been considered meaningless for FL. Bulk FL tumors were thought to generally resemble normal GC clear-zone B cells, based on similarities observed in their gene expression profiles (Non-Patent Literature 16). Nevertheless, pioneering epigenetic analyses have provided some clues toward putative COO subtyping of FL tumors, namely subtyping between "GCB center cell-like" subtypes and "in vitro activated plasmablast-like" subtypes (Non-Patent Literature 17).

[0007] This appeared consistent with observations regarding a minor subset of FL tumors without BCL2 rearrangement showing enrichment of ABC-like signatures (Non-Patent Literature 18) or observations regarding a minor subset of FL tumors without BCL2 rearrangement showing microRNA profiles associated with a “late” GC B cell phenotype with increased IRF4 / MUM1 expression (Non-Patent Literature 19). This is also supported by recent observations regarding discontinuous stages of plasmablast differentiation starting from a subset of clear-zone GC B cells and distinct subpopulations consisting of memory B cell precursors within the GC (Non-Patent Literature 20). Furthermore, recent meta-analysis studies have suggested that COO-based classification of FL may have prognostic importance and that ABC-like signatures correlated with poor survival (Non-Patent Literature 21). [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Gupta et al.,Am J Blood Res.2022 Aug 15;12(4):105-124 [Non-Patent Document 2] Rodriguez-Sevilla et al.,Evaluation of four prognostic indices in follicular lymphoma treated in first line with immunochemotherapy,Blood Adv.2022 Oct 19 [Non-Patent Document 3] Dave et al.,N Engl J Med.,2004 Nov.18;351(21):2159-2169 [Non-Patent Document 4] Xerri et al.,Hum. Pathol.2017 June;64:128-136 [Non-Patent Document 5] Bolen 2017 et al.,Blood Adv.2017 Sept.27;1(22):1884-1890 [Non-licensed Document 6] Araujo-Ayala et al.,Hematol.Oncol.2021 June:Suppl 1:83-87 [Non-licensed Document 7] Tobin et al.,2019 Dec.1;37(34):3300-3309 [Non-licensed Document 8] Bolen et al.,2021 May 13;137(19):2704-2707 [Non-licensed Document 9] Pastore et al.,Lancet Oncol.2015 Sept;16(9):1111-1122 [Non-licensed Document 10] Huet et al.,Erratum in:Lancet Oncol.2018 Jun;19(6):e283 [Non-licensed Document 11] Mottock et al., Blood 2018 Jan 11;131(2):226-235 [Non-licensed Document 12] Silva et al.,Haematologica 2019 Jun;104(6):e252-255 [Non-licensed Document 13] Schmitz et al.,N Engl J Med.,2018 Apr 12;378(15):1396-1407 [Non-licensed Document 14] Wienand et al.,Hematol Oncol.2021 Jun;39 suppl 1:24-30 [Non-licensed Document 15] Wright et al. Cancer Cell 2020 Apr 13;37(4):551-568 [Non-licensed Document 16] Victora et al.Blood 2012 Sep 13;120(11):2240-2248 [Non-licensed Document 17] Koues et al., Immunity 2015 Jan 20;42(1):186-198 [Non-Patent Document 18] Leich et al., Blood 2009 Jul 23;114(4):826-834 [Non-Patent Document 19] Leich et al., Blood 2011 Nov 17;118(2)\5550-5558 [Non-Patent Document 20] [[ID=>

非特許文献21

[0009] There remains a significant need for an effective method for classifying subtypes of FL and predicting sensitivity to treatment. [[ID=]] [Means for Solving the Problems]

[0010] In one aspect, provided herein is a method for identifying that a subject has activated / memory B cell-like (ABC / MEM-like) follicular lymphoma (FL), comprising: (a) determining the gene expression level of at least one biomarker in a sample from the subject, wherein the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1; (b) determining a composite score based on the gene expression level of the at least one biomarker; and (c) identifying, based on the composite score, that the subject has ABC / MEM-like FL.​

[0011] In certain embodiments, the method further comprises treating subjects identified as having ABC / MEM-like FL with a therapeutically effective dose of an immunomodulator (IMiD®) and / or a cereblon E3 ligase modulating compound.

[0012] In another embodiment, the foregoing provides a method for selectively treating a subject having FL, comprising: (a) determining the gene expression level of at least one biomarker in a sample of the subject, the biomarker being selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138 and SHCBP1; (b) determining a composite score based on the gene expression level of at least one biomarker; (c) identifying the subject as having ABC / MEM-like FL based on the composite score; and (d) treating the subject identified as having ABC / MEM-like FL with a therapeutically effective amount of IMiD® and / or a cereblon E3 ligase modulating compound.

[0013] In another embodiment, the Specified Provision is a method for identifying a subject likely to be responsive to treatment for ABC / MEM-like FL, or for predicting the responsiveness of a subject to treatment for ABC / MEM-like FL, comprising: (a) determining the gene expression level of at least one biomarker in a sample of the subject, the biomarker being selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1; (b) determining a composite score based on the gene expression level of at least one biomarker; and (c) identifying or predicting, based on the composite score, that the subject is likely to be responsive to treatment for ABC / MEM-like FL, wherein the treatment for ABC / MEM-like FL comprises a therapeutically effective amount of IMiD® and / or a cereblon E3 ligase modulating compound. In certain embodiments, the method further includes administering ABC / MEM-like FL treatment to subjects who are likely to be responsive to ABC / MEM-like FL treatment.

[0014] In certain embodiments, IMiD® is selected from the group consisting of lenalidomide, pomalidomide and thalidomide, and their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions and pharmaceutically acceptable salts. In certain embodiments, the cerebron E3 ligase modulating compound is iverdamide and formula (I) [ka] The compounds are selected from the group consisting of the following: compounds and their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions and pharmaceutically acceptable salts. In certain embodiments, the IMiD® and / or cereblon E3 ligase modulating compounds are lenalidomide, pomalidomide, thalidomide, iverdamide and formula (I) [ka] The compounds are selected from the group consisting of the following: compounds, their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions, and pharmaceutically acceptable salts.

[0015] In certain embodiments, treatment of ABC / MEM-like FL further comprises a therapeutically effective dose of anti-CD20 antibody. In certain embodiments, the anti-CD20 antibody is selected from the group consisting of rituximab, obinutuzumab, ocrelizumab, and combinations thereof.

[0016] In certain embodiments, the treatment of ABC / MEM-like FL comprises a therapeutically effective amount of rituximab and lenalidomide or its enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions or pharmaceutically acceptable salts. In certain embodiments, the treatment of ABC / MEM-like FL comprises a therapeutically effective amount of rituximab and formula (I) [ka] This includes compounds thereof, their enantiomers, mixtures of enantiomers, tautomers, isotope substitutions, or pharmaceutically acceptable salts.

[0017] In certain embodiments, treatment of ABC / MEM-like FL improves overall survival, PFS, and / or FFS in subjects with ACB / MEM-like FL.

[0018] In certain embodiments, the composite score is determined based on the gene expression levels of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1. In certain embodiments, the composite score is determined based on the sum of the weighted gene expression levels of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1. In certain embodiments, the composite score is calculated using the following formula: (-12.90235 × TTC28 gene expression level) + (-17.20497 × FOXP1 gene expression level) + (-14.08426 × DOPEY2 gene expression level) + (-14.14635 × IQSEC1 gene expression level) + (-15.78924 × PTPRJ gene expression level) + (-13.44714 × SLA gene expression level) + (-13.21572 × CXXC5 gene expression level) + (-14.31872 × PDE4B gene expression level) + (-18.17919 × TCF4 gene expression level) + (-16.21973 × MPEG1 gene expression level) The level is determined based on the following: (Current level) + (15.81861 × KIAA1211 gene expression level) + (15.97033 × SCPEP1 gene expression level) + (17.50829 × RASL11A gene expression level) + (17.18333 × LMO2 gene expression level) + (15.22055 × HS2ST1 gene expression level) + (15.22908 × ENPP3 gene expression level) + (15.60008 × SH3RF1 gene expression level) + (18.07827 × SCIMP gene expression level) + (15.04494 × CCDC138 gene expression level) + (15.84456 × SHCBP1 gene expression level).

[0019] In certain embodiments, if the composite score is lower than a predetermined value, the subject is identified as having ABC / MEM-like FL or is identified or predicted to be likely to respond to treatment for ABC / MEM-like FL, and optionally the predetermined value is zero. In certain embodiments, if the composite score is lower than a reference score, the subject is identified as having ABC / MEM-like FL or is identified or predicted to be likely to respond to treatment for ABC / MEM-like FL. In certain embodiments, the reference score is derived from a healthy subject or a population of healthy subjects and is calculated in the same manner as the composite score.

[0020] In another embodiment, the method provided herein is for identifying a subject as having germinal center B-cell-like (GCB-like) follicular lymphoma (FL), comprising: (a) determining the gene expression level of at least one biomarker in a sample from the subject, wherein the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1; (b) determining a composite score based on the gene expression level of at least one biomarker; and (c) identifying the subject as having GCB-like FL based on the composite score. In certain embodiments, the method further comprises administering treatment for GCB-like FL to the subject identified as having GCB-like FL.

[0021] In another embodiment, the foregoing provides a method for selectively treating a subject having FL, comprising: (a) determining the gene expression level of at least one biomarker in a sample of the subject, wherein the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138 and SHCBP1; (b) determining a composite score based on the gene expression level of at least one biomarker; (c) identifying the subject as having GCB-like FL based on the composite score; and (d) administering a therapeutically effective dose of GCB-like FL treatment to the subject identified as having GCB-like FL.

[0022] In another embodiment, the Specified Method for identifying a subject likely to be responsive to GCB-like FL treatment or for predicting the responsiveness of a subject to GCB-like FL treatment, comprising: (a) determining the gene expression level of at least one biomarker in a sample of the subject, the biomarker being selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138 and SHCBP1; (b) determining a composite score based on the gene expression level of at least one biomarker; and (c) identifying or predicting, based on the composite score, that the subject is likely to be responsive to GCB-like FL treatment. In certain embodiments, the Method further comprises administering GCB-like FL treatment to a subject likely to be responsive to GCB-like FL treatment.

[0023] In certain embodiments, the treatment of GCB-like FL comprises a therapeutically effective dose of IMiD®, a cereblon E3 ligase-modified compound, an anti-CD20 antibody, a chemotherapeutic agent, or a combination thereof.

[0024] In certain embodiments, IMiD® and / or Cereblon E3 ligase modulating compounds include lenalidomide, pomalidomide, thalidomide, iverdomide and formula (I) [ka] The compounds are selected from the group consisting of the following: compounds, their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions, and pharmaceutically acceptable salts.

[0025] In certain embodiments, the anti-CD20 antibody is selected from the group consisting of rituximab, obinutuzumab, ocrelizumab, and combinations thereof.

[0026] In certain embodiments, the chemotherapeutic agent is selected from the group consisting of cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and combinations thereof.

[0027] In certain embodiments, treatment for GCB-like FL includes a therapeutically effective dose of an anti-CD20 antibody and a chemotherapeutic agent. In certain embodiments, treatment for GCB-like FL includes a therapeutically effective dose of rituximab, cyclophosphamide, doxorubicin hydrochloride, and vincristine sulfate. In certain embodiments, treatment for GCB-like FL includes a therapeutically effective dose of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone.

[0028] In certain embodiments, the treatment of GCB-like FL comprises a therapeutically effective amount of IMiD® and an anti-CD20 antibody. In certain embodiments, the treatment of GCB-like FL comprises a therapeutically effective amount of rituximab and lenalidomide or its enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions, or pharmaceutically acceptable salts.

[0029] In certain embodiments, treatment of GCB-like FL involves a therapeutically effective dose of rituximab and formula (I) [ka] This includes compounds thereof, their enantiomers, mixtures of enantiomers, tautomers, isotope substitutions, or pharmaceutically acceptable salts.

[0030] In certain embodiments, the composite score is determined based on the gene expression levels of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1. In certain embodiments, the composite score is determined based on the sum of the weighted gene expression levels of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1. In certain embodiments, the composite score is calculated using the following formula: (-12.90235 × TTC28 gene expression level) + (-17.20497 × FOXP1 gene expression level) + (-14.08426 × DOPEY2 gene expression level) + (-14.14635 × IQSEC1 gene expression level) + (-15.78924 × PTPRJ gene expression level) + (-13.44714 × SLA gene expression level) + (-13.21572 × CXXC5 gene expression level) + (-14.31872 × PDE4B gene expression level) + (-18.17919 × TCF4 gene expression level) + (-16.21973 × MPEG1 gene expression level) The level is determined based on the following: (Current level) + (15.81861 × KIAA1211 gene expression level) + (15.97033 × SCPEP1 gene expression level) + (17.50829 × RASL11A gene expression level) + (17.18333 × LMO2 gene expression level) + (15.22055 × HS2ST1 gene expression level) + (15.22908 × ENPP3 gene expression level) + (15.60008 × SH3RF1 gene expression level) + (18.07827 × SCIMP gene expression level) + (15.04494 × CCDC138 gene expression level) + (15.84456 × SHCBP1 gene expression level).

[0031] In certain embodiments, if the composite score is higher than a predetermined value, the subject is identified as having GCB-like FL, or is identified or predicted to be likely to respond to treatment for GCB-like FL, and optionally the predetermined value is zero. In certain embodiments, if the composite score is higher than a reference score, the subject is identified as having GCB-like FL, or is identified or predicted to be likely to respond to treatment for GCB-like FL. In certain embodiments, the reference score is derived from a healthy subject or a population of healthy subjects and is calculated in the same manner as the composite score.

[0032] In certain embodiments, the gene expression level of at least one biomarker is at the mRNA level. In certain embodiments, the gene expression level is measured by RNA sequencing. In certain embodiments, the gene expression level is measured by a PCR-based quantification method.

[0033] In another embodiment, the foregoing provides a method for identifying a subject as having ABC / MEM-like FL, comprising (a) determining the protein expression levels of FOXP1, LMO2, CD22, and MUM1; and (b) identifying the subject as having ABC / MEM-like FL based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1. In certain embodiments, the method further comprises administering a therapeutically effective dose of an immunomodulator (IMiD®) and / or a cerebron E3 ligase modulating compound to a subject identified as having ABC / MEM-like FL.

[0034] In another embodiment, the foregoing provides a method for selectively treating a subject having FL, comprising: (a) determining the protein expression levels of FOXP1, LMO2, CD22, and MUM1; (b) identifying the subject as having ABC / MEM-like FL based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1; and (c) administering a therapeutically effective dose of IMiD® and / or a cereblon E3 ligase modifier compound to the subject identified as having ABC / MEM-like FL.

[0035] In another embodiment, the herein provides a method for identifying a subject likely to be responsive to ABC / MEM-like FL treatment or for predicting the responsiveness of a subject to ABC / MEM-like FL treatment, comprising: (a) determining the protein expression levels of FOXP1, LMO2, CD22, and MUM1; and (b) identifying or predicting, based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1, that the subject is likely to be responsive to ABC / MEM-like FL treatment, wherein the ABC / MEM-like FL treatment comprises IMiD® and / or a cereblon E3 ligase modulating compound. In certain embodiments, the method further comprises administering ABC / MEM-like FL treatment to a subject likely to be responsive to ABC / MEM-like FL treatment.

[0036] In certain embodiments, IMiD® and / or Cereblon E3 ligase modulating compounds include lenalidomide, pomalidomide, thalidomide, iverdomide and formula (I) [ka] The compounds are selected from the group consisting of the following: compounds, their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions, and pharmaceutically acceptable salts.

[0037] In certain embodiments, treatment of ABC / MEM-like FL further comprises a therapeutically effective dose of anti-CD20 antibody. In certain embodiments, the anti-CD20 antibody is selected from the group consisting of rituximab, obinutuzumab, ocrelizumab, and combinations thereof.

[0038] In certain embodiments, the treatment of ABC / MEM-like FL comprises a therapeutically effective amount of rituximab and lenalidomide or its enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions or pharmaceutically acceptable salts. In certain embodiments, the treatment of ABC / MEM-like FL comprises a therapeutically effective amount of rituximab and formula (I) [ka] This includes compounds thereof, their enantiomers, mixtures of enantiomers, tautomers, isotope substitutions, or pharmaceutically acceptable salts.

[0039] In certain embodiments, treatment of ABC / MEM-like FL improves overall survival, PFS, and / or FFS in subjects with ACB / MEM-like FL.

[0040] In certain embodiments, the protein expression levels of FOXP1, LMO2, CD22, and MUM1 are expressed at the protein level. In certain embodiments, the protein level is measured using immunohistochemistry (IHC). In certain embodiments, the protein level is measured using other antibody-based imaging and quantification methods, such as multiplex ion beam imaging (MIBI) and imaging mass cytometry (IMC).

[0041] In certain embodiments, if (i) the protein expression level of FOXP1 is strong or moderate and the protein expression level of LMO2 is weak or negative, (ii) the protein expression level of FOXP1 is close to (equally strong, moderate or weak) the protein expression level of LMO2 or otherwise of no informational value and the protein expression level of CD22 is weak, or (iii) the protein expression level of FOXP1 is close to (equally strong, moderate or weak) the protein expression level of LMO2 or otherwise of no informational value and the protein expression level of CD22 is moderate or otherwise of no informational value, and the percentage of MUM1-positive cells in the sample is greater than approximately 15%, then the subject is identified as having ABC / MEM-like FL, or is identified or predicted to be likely to respond to treatment for ABC / MEM-like FL.

[0042] In certain embodiments, (i) the percentage of FOXP1-positive cells in the sample is greater than approximately 50%, and the percentage of LMO2-positive cells in the sample is less than approximately 50%, and the difference between the percentage of FOXP1-positive cells and the percentage of LMO2-positive cells in the sample is about 20% or more; (ii) the difference between the percentage of FOXP1-positive cells and the percentage of LMO2-positive cells in the sample is less than approximately 20%, and the percentage of CD22-positive cells in the sample If the stage is less than approximately 20%, or (iii) if the difference between the percentage of FOXP1-positive cells in the sample and the percentage of LMO2-positive cells in the sample is less than approximately 20%, and the percentage of CD22-positive cells in the sample is between approximately 20% and 80%, and the percentage of MUM1-positive cells in the sample is greater than approximately 15%, then the subject is identified as having ABC / MEM-like FL, or is identified or predicted to be likely to respond to treatment for ABC / MEM-like FL.

[0043] In another embodiment, the foregoing provides a method for identifying a subject to have GCB-like FL, comprising (a) determining the protein expression levels of FOXP1, LMO2, CD22, and MUM1; and (b) identifying the subject to have GCB-like FL based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1.

[0044] In certain embodiments, the method further includes treating a subject identified as having GCB-like FL with GCB-like FL.

[0045] In another embodiment, the foregoing provides a method for selectively treating a subject having FL, comprising: (a) determining the protein expression levels of FOXP1, LMO2, CD22, and MUM1; (b) identifying the subject as having GCB-like FL based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1; and (c) administering a therapeutically effective dose of GCB-like FL treatment to the subject identified as having GCB-like FL.

[0046] In another embodiment, the foregoing provides a method for identifying subjects likely to be responsive to GCB-like FL treatment or for predicting the responsiveness of subjects to GCB-like FL treatment, comprising: (a) determining the protein expression levels of FOXP1, LMO2, CD22 and MUM1; (b) identifying or predicting, based on the protein expression levels of FOXP1, LMO2, CD22 and MUM1, that subjects are likely to be responsive to GCB-like FL treatment; and optionally, (c) administering GCB-like FL treatment to subjects likely to be responsive to GCB-like FL treatment.

[0047] In another embodiment, provided herein is a method for identifying subjects likely to be responsive to GCB-like FL treatment, or predicting the responsiveness of subjects to GCB-like FL treatment, when (i) the protein expression level of LMO2 is strong or moderate and the protein expression level of FOXP1 is weak or negative; (ii) the protein expression level of LMO2 is close to (equally strong, moderate or weak) or otherwise of no informational value, and the protein expression level of CD22 is strong; or (iii) the protein expression level of LMO2 is close to (equally strong, moderate or weak) or otherwise of no informational value, and the protein expression level of CD22 is moderate or otherwise of no informational value, and the percentage of MUM1-positive cells in the sample is less than approximately 10%.

[0048] In certain embodiments, (i) the percentage of LMO2-positive cells in the sample is greater than approximately 50%, and the percentage of FOXP1-positive cells in the sample is less than approximately 50%, and the difference between the percentage of LMO2-positive cells in the sample and the percentage of FOXP1-positive cells in the sample is about 20% or more; (ii) the difference between the percentage of FOXP1-positive cells in the sample and the percentage of LMO2-positive cells in the sample is less than approximately 20%, and the CD22 cells in the sample are If the percentage is greater than approximately 80%, or (iii) if the difference between the percentage of FOXP1-positive cells in the sample and the percentage of LMO2-positive cells in the sample is less than approximately 20%, the percentage of CD22-positive cells in the sample is between approximately 20% and approximately 80%, and the percentage of MUM1-positive cells in the sample is less than approximately 10%, then the subject is identified as having GCB-like FL, or is identified or predicted to be highly responsive to treatment for GCB-like FL.

[0049] In certain embodiments, the treatment of GCB-like FL comprises a therapeutically effective dose of IMiD®, a cereblon E3 ligase-modified compound, an anti-CD20 antibody, a chemotherapeutic agent, or a combination thereof.

[0050] In certain embodiments, IMiD® and / or Cereblon E3 ligase modulating compounds include lenalidomide, pomalidomide, thalidomide, iverdomide and formula (I) [ka] The compounds are selected from the group consisting of the following: compounds, their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions, and pharmaceutically acceptable salts.

[0051] In certain embodiments, the anti-CD20 antibody is selected from the group consisting of rituximab, obinutuzumab, ocrelizumab, and combinations thereof.

[0052] In certain embodiments, the chemotherapeutic agent is selected from the group consisting of cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and combinations thereof.

[0053] In certain embodiments, treatment of GCB-like FL comprises a therapeutically effective dose of anti-CD20 antibody and a chemotherapeutic agent.

[0054] In certain embodiments, the treatment of GCB-like FL comprises a therapeutically effective dose of rituximab, cyclophosphamide, doxorubicin hydrochloride, and vincristine sulfate. In certain embodiments, the treatment of GCB-like FL comprises a therapeutically effective dose of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone.

[0055] In certain embodiments, the treatment of GCB-like FL comprises a therapeutically effective amount of IMiD® and an anti-CD20 antibody. In certain embodiments, the treatment of GCB-like FL comprises a therapeutically effective amount of a cereblon E3 ligase-modulating compound and an anti-CD20 antibody.

[0056] In certain embodiments, the treatment of GCB-like FL comprises a therapeutically effective amount of rituximab and lenalidomide or its enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions, or pharmaceutically acceptable salts.

[0057] In certain embodiments, treatment of GCB-like FL involves a therapeutically effective dose of rituximab and formula (I) [ka] This includes compounds thereof, their enantiomers, mixtures of enantiomers, tautomers, isotope substitutions, or pharmaceutically acceptable salts.

[0058] In certain embodiments, the protein expression levels of FOXP1, LMO2, CD22, and MUM1 are at the protein level.

[0059] In certain embodiments, protein levels are measured using immunohistochemistry (IHC). In certain embodiments, protein levels are measured using other antibody-based imaging and quantification methods, such as multiplex ion beam imaging (MIBI) and imaging mass cytometry (IMC).

[0060] In certain embodiments, the sample is a tumor biopsy.

[0061] In another embodiment, provided herein is a kit for carrying out the methods disclosed herein, the kit comprising (i) the gene expression level of at least one biomarker selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138 and SHCBP1, or (ii) a drug for determining the protein expression levels of FOXP1, LMO2, CD22 and MUM1.

[0062] In certain embodiments, the kit further includes equipment for obtaining a sample. In certain embodiments, the kit further includes instructions for interpreting the determined expression levels. [Brief explanation of the drawing]

[0063] [Figure 1] This heatmap shows a 20-gene-based linear predictor score (LPS20) that classifies patients based on whether they are activated / memory B-cell-like (ABC / MEM-like) (indicated by thick arrows) FL or germinal center B-cell-like (GCB-like FL) (indicated by thin arrows). [Figure 2A] The graphs show progression-free survival (PFS) curves for ABC / MEM-like patients (indicated by thick arrows) and GCB-like patients (indicated by thin arrows) treated with rituximab plus chemotherapy (R-chemotherapy), such as cyclophosphamide, doxorubicin, and hydrochloride (R-CHOP). [Figure 2B]The PFS curves for ABC-MEM-like patients (indicated by thick arrows) and GCB-like patients (indicated by thin arrows) treated with the lenalidomide + rituximab combination (R2, also disclosed herein as R+R) are shown. [Figure 3A] The PFS curves for ABC / MEM-like patients (indicated by thick arrows) and GCB-like patients (indicated by thin arrows) in the PRIMA FL cohort treated with R-chemotherapy are shown. [Figure 3B] The FFS curves for ABC / MEM-like patients (indicated by thick arrows) and GCB-like patients (indicated by thin arrows) in the BCCA FL cohort treated with R-chemotherapy are shown. [Figure 4] This shows the mutation profiles in ABC / MEM-like patients compared to GCB-like patients. [Figure 5] The diagram shows the algorithm used to subtype formalin-fixed paraffin-embedded (FFPE) FL biopsies. [Figure 6A] The immunohistochemistry (IHC) of FOXP1 and LMO2 in whole sections of FFPE biopsy specimens classified as ABC / MEM-like FL (strong staining of FOXP1 and weak staining of LMO2) is shown. [Figure 6B] The immunohistochemistry (IHC) of FOXP1 and LMO2 in whole sections of FFPE biopsy specimens classified as GCB-like FL (weak staining of FOXP1 and strong staining of LMO2) is shown. [Figure 7A] The immunohistochemistry (IHC) of FOXP1, LMO2, CD22, and MUM1 in whole sections of FFPE biopsy specimens classified as GCB-like FL (weak staining of FOXP1, strong staining of LMO2, strong staining of CD22, and weak staining of MUM1) is shown. [Figure 7B] The immunohistochemistry (IHC) of FOXP1, LMO2, CD22, and MUM1 in all sections of FFPE biopsy specimens classified as ABC / MEM-like FL (moderate staining of FOXP1, moderate staining of LMO2, weak staining of CD22, and staining of MUM1 in 10% to 15% of cells) is shown. [Figure 8]The immunohistochemistry (IHC) of FOXP1, LMO2, CD22, and MUM1 in whole sections of FFPE biopsy specimens is shown. [Modes for carrying out the invention]

[0064] Provided herein is a method using specific biomarkers to identify subtypes of follicular lymphoma, selectively treat subtypes of follicular lymphoma, identify subjects likely to be responsive to FL treatment, and predict the responsiveness of subjects to FL treatment. This involves the finding that the expression levels of specific biomarkers (e.g., mRNA levels, protein levels) were associated with subtypes of follicular lymphoma (e.g., ACE / MEM-like follicular lymphoma and GCB-like follicular lymphoma) and that patients with ACE / MEM-like follicular lymphoma were a high-risk subgroup with a poorer outcome when treated with R-chemotherapy (rituximab + chemotherapy), but R 2 This finding is partly based on the fact that this was not the case when treated with (lenalidomide + rituximab).

[0065] 5.1 Definition As used herein and unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” refer to any action taken while a patient has a given cancer (for example, a given type of follicular lymphoma, e.g., ACE / MEM-like follicular lymphoma, GCB-like follicular lymphoma) to reduce the severity of the cancer or to slow or delay its progression.

[0066] As used herein, the terms “compound” and “therapeutic compound” are interchangeable and include the compound of formula (I) or its tautomers, isotope substitutions, or pharmaceutically acceptable salts. It should be understood that the compounds provided herein may contain a chiral center. Such a chiral center may be either the (R) configuration or the (S) configuration, or a mixture thereof. It should be understood that the chiral center of the compounds provided herein may undergo epimerization in vivo. Therefore, those skilled in the art will recognize that for compounds undergoing epimerization in vivo, the administration of the (R) form of the compound is equivalent to the administration of the (S) form. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or they may be separated using conventional techniques such as chromatography on a chiral stationary phase. In the description herein, if there is any discrepancy between a chemical name and a chemical structure, the structure shall prevail.

[0067] The terms "sensitivity" or "being susceptible," when used in reference to cancer treatment, are relative terms referring to the degree of effectiveness of a cancer treatment in reducing or mitigating the progression of the tumor or cancer being treated. For example, the term "increased sensitivity," when used in reference to the treatment of cells or tumors associated with a compound, refers to an increase of at least about 5% or more in the effectiveness of the cancer treatment.

[0068] As used herein and unless otherwise specified, the term “therapeutic dose” in the context of cancer treatment (e.g., immunomodulatory drugs (IMiD®)) is sufficient to produce a therapeutic benefit in the treatment or management of cancer, or to delay or minimize one or more symptoms associated with the presence of cancer. A therapeutic dose of a compound means the amount of the agent, alone or in combination with other therapies, that produces a therapeutic benefit in the treatment or management of cancer. The term “therapeutic dose” may include amounts that improve the overall therapy, reduce or avoid the symptoms or causes of cancer, or enhance the therapeutic effectiveness of another agent. The term also refers to amounts of the compound sufficient to elicit a biological or medical response in a biomolecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, as sought by a researcher, veterinarian, physician, or clinician.

[0069] The terms “responsiveness” or “responsiveness,” when used in relation to cancer treatment (e.g., IMiD®), refer to the degree of effectiveness of the treatment in reducing or alleviating the symptoms of the cancer being treated, e.g., follicular lymphoma. For example, the term “increased responsiveness,” when used in relation to the treatment of cells or subjects, refers to an increase in effectiveness in reducing or alleviating the symptoms of the disease compared to a reference treatment (e.g., treatment of the same cells or subjects or treatment of different cells or subjects), as measured using any method known in the art. In certain embodiments, the increase in effectiveness is at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%.

[0070] As used herein, the terms “effective target response,” “effective patient response,” and “effective patient tumor response” refer to any increase in the therapeutic benefit to the patient. “Effective patient tumor response” could be, for example, a reduction of about 5%, about 10%, about 25%, about 50%, or about 100% in the rate of tumor progression. “Effective patient tumor response” could also be, for example, a reduction of about 5%, about 10%, about 25%, about 50%, or about 100% in the physical symptoms of cancer. “Effective patient tumor response” could also be an increase of, for example, about 5%, about 10%, about 25%, about 50%, about 100%, about 200%, or more in the patient response as measured by any preferred means such as gene expression, cell count, assay results, or tumor size.

[0071] Improvement in cancer (e.g., follicular lymphoma or its subtypes) or cancer-related diseases can be characterized as a complete response or a partial response. “Complete response” means the absence of clinically detectable disease and the normalization of all previously abnormal radiological findings, bone marrow and cerebrospinal fluid (CSF) measurements, or abnormal monoclonal protein levels. “Partial response” means a reduction of at least approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in all measurable tumor volume (i.e., the number of malignant cells present in the subject, or the size of the measured tumor mass, or the amount of abnormal monoclonal protein) in the absence of new lesions. The term “treatment” refers to both complete and partial responses.

[0072] The term "prospect" generally refers to an increase in the probability of a certain event. When used in relation to the effectiveness of a patient tumor response, the term "prospect" generally refers to an increase in the probability of a decrease in the rate of tumor progression or the rate of tumor cell proliferation. When used in relation to the effectiveness of a patient tumor response, the term "prospect" may also generally mean an increase in indicators such as mRNA expression or protein expression that may demonstrate enhanced progress in tumor treatment.

[0073] The term “predict” generally means to determine or communicate in advance. For example, when used to “predict” the effectiveness of a cancer treatment (e.g., IMiD®), the term “predict” may mean that the prospects for the outcome of the cancer treatment can be determined at an initial point before treatment begins or before the treatment period has substantially progressed.

[0074] A "biological marker" or "biomarker" is a substance whose detection indicates a specific biological condition, such as the presence of a certain type of cancer. In certain embodiments, biomarkers may be determined individually. In other embodiments, several biomarkers may be measured simultaneously.

[0075] As used herein, the term “source” refers to the origin of the sample when used in relation to a reference sample. For example, a sample taken from blood would have a reference sample taken from blood. Similarly, a sample taken from bone marrow would have a reference sample taken from bone marrow.

[0076] The terms “expressed” or “expression,” as used herein, refer to the transcription from a gene in which at least a portion of one of the two nucleic acid strands of the gene yields an RNA nucleic acid molecule that is complementary to a region of that strand. The terms “expressed” or “expression,” as used herein, also refer to the translation from an RNA molecule that yields a protein, polypeptide, or a portion thereof. A “biological marker” or “biomarker” is a substance whose detection indicates a particular biological condition, such as the presence of a certain type of cancer. In certain embodiments, biomarkers may be determined individually. In other embodiments, several biomarkers may be measured simultaneously.

[0077] As used interchangeably herein, the terms “polypeptide” and “protein” refer to polymers consisting of three or more amino acids linked by peptide bonds in a continuous sequence. The term “polypeptide” includes proteins, protein fragments, protein analogs, oligopeptides, and the like. As used herein, the term “polypeptide” may also refer to peptides. The amino acids constituting a polypeptide may be of natural origin or synthetic. Polypeptides may be purified from biological samples. Polypeptides, proteins, or peptides also include modified polypeptides, proteins, and peptides, such as glycopolypeptides, glycoproteins, or glycopeptides, or lipopolypeptides, lipoproteins, or lipopeptides.

[0078] In certain embodiments, the "biomarker" indicates a change in mRNA expression level that may correlate with the risk or progression of the disease or the susceptibility to a given treatment. In certain embodiments, the biomarker is a nucleic acid such as mRNA or cDNA.

[0079] In additional embodiments, the “biomarker” indicates a change in the level of polypeptide or protein expression that may correlate with the risk or progression of a disease or the patient’s sensitivity to treatment. In certain embodiments, the biomarker may be a polypeptide, a protein, or a fragment thereof. The relative level of a given protein can be determined by methods known in the art. For example, antibody-based methods such as immunoblotting, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), or other methods may be used.

[0080] The term "level" refers to the quantity, accumulation, or rate of molecules. Levels can be expressed, for example, by the amount or rate of synthesis of gene-encoded messenger RNA (mRNA), gene-encoded polypeptides or proteins, or the amount or rate of synthesis of biomolecules accumulating within cells or in biological fluids. The term "level" also refers to the absolute or relative amount of molecules present in a sample, determined under steady-state or transient conditions.

[0081] The terms “determining,” “measuring,” “assessing,” “evaluating,” and “assaying,” as used herein, generally refer to any form of measurement and include determining whether or not a certain element is present. These terms include quantitative and / or qualitative determinations. Evaluation can be relative or absolute.

[0082] As used herein and unless otherwise indicated, the term “pharmaceutically acceptable salt” encompasses non-toxic acid and base addition salts of the compound referred to by this term. Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids known in the art, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embolic acid, and enanthic acid. Compounds that are essentially acidic can form salts with a variety of pharmaceutically acceptable bases. Bases that can be used to prepare pharmaceutically acceptable base addition salts of such acidic compounds include, but are not limited to, non-toxic base addition salts, i.e., alkali metal salts or alkaline earth metal salts (especially calcium, magnesium, sodium, or potassium salts), and bases that form salts containing pharmaceutically acceptable cations. Suitable organic bases include, but are not limited to, N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine, and procaine.

[0083] As used herein and unless otherwise indicated, the term “solvate” means a compound or a salt thereof provided herein, further comprising a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent intermolecular forces. If the solvent is water, the solvate is a hydrate.

[0084] As used herein and unless otherwise specified, the term “stereoisomer” encompasses all enantiomers / stereoisomerically pure compounds and enantiomers / stereoisomerically concentrated compounds of the present invention.

[0085] As used herein and unless otherwise indicated, the terms “stereoisomer” or “stereoisomerically pure” mean one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center substantially does not contain the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers substantially does not contain other diastereomers of that compound. Typical stereoisomerically pure compounds include more than about 80 wt% of one stereoisomer of the compound and less than about 20 wt% of other stereoisomers of the compound, more than about 90 wt% of one stereoisomer of the compound and less than about 10 wt% of other stereoisomers of the compound, more than about 95 wt% of the compound and less than about 5 wt% of other stereoisomers of the compound, or more than about 97 wt% of one stereoisomer of the compound and less than about 3 wt% of other stereoisomers of the compound. The compounds may have a chiral center and may exist as racemates, individual enantiomers, or diastereomers, or mixtures thereof. All such isomeric forms, including mixtures thereof, are included in the embodiments provided herein.

[0086] As used herein, the term "tautomer" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms may depend on the environment in which the compound is found, for example, whether the compound is a solid or in an organic solution or aqueous solution. For example, in aqueous solution, pyrazole exists in the following isomeric forms: [ka] They can exhibit this characteristic, which is referred to as a tautomer.

[0087] Unless otherwise specifically stated, if a compound can take on alternative tautomers, regioisomers, and / or stereoisomers, all alternative isomers are intended to be encompassed within the scope of the claimed subject matter. For example, if a compound can have one of two tautomers, both tautomers are intended to be encompassed herein. Thus, the compounds provided herein may be enantiomerically pure or may be mixtures of stereoisomers or diastereomers. As used herein and unless otherwise indicated, the term “enantiomerically pure” means a stereoisomerically pure composition of a compound having one chiral center.

[0088] The use of stereoisomerically pure forms of such compounds and mixtures of those forms are included in the embodiments provided herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound may be used in the methods and compositions provided herein. Such isomers may be synthesized asymmetrically or resolved using standard techniques such as chiral columns or chiral resolving agents. For example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen, SH, et al., Tetrahedron 33:2725 (1977), Eliel, EL, Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962), Wilen, SH, Tables of Resolving Agents and Optical Resolutions. p.268(ELEliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN,1972),Todd,M.,Separation Of Enantiomers:Synthetic Methods(Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2014),Toda,F.,Enantiomer Separation:Fundamentals and Practical Methods(Springer Science&Business See Media, 2007; Subramanian, G., Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); and Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0089] As used herein, “isotopolog” or “isotopologue” refers to an isotope-enriched compound. The term “isotopically enriched” refers to an atom or compound having an isotope composition other than that of the atom or compound’s natural isotope composition. Radiolabeled and isotope-enriched compounds are useful as therapeutic agents (e.g., hematological and anti-inflammatory agents), research reagents (e.g., binding assay reagents), and diagnostic agents (e.g., in vivo contrast agents). All isotope variations of the compounds described herein, whether radioactive or not, are intended to be included within the scope of the embodiments provided herein. Exemplary isotope substitutions include compounds enriched with deuterium, carbon-13, or nitrogen-15. For example, an isotope substitution may be a deuterium-enriched compound, such as compound 1, 2, or 3, where deuteration occurs at the chiral center.

[0090] The terms “about” or “approximately” mean an acceptable error of a particular value, as determined by those skilled in the art, which in part depends on how that value is measured or determined. In certain embodiments, the terms “about” or “approximately” mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms “about” or “approximately” mean within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0091] The use of the words "a" or "an" may mean "one" when used in conjunction with the term "including" in the claims and / or herein, but also coincides with the meanings of "one or more," "at least one," and "one or more."

[0092] As used herein, unless otherwise specified or indicated by the context, the term “pre-treatment” as used in accordance with the methods described herein means the period before the administration of treatment.

[0093] As used herein, the terms “patient” and “subject” refer to animals such as mammals. In certain embodiments, the patient or subject is a human. In other embodiments, the patient or subject is a non-human animal such as a dog, cat, livestock (e.g., horse, pig, or donkey), chimpanzee, or monkey. In specific embodiments, the patient or subject is a human having follicular lymphoma (e.g., ABC / MEM-like FL) requiring treatment.

[0094] 5.2 Methods for identifying and treating subtypes of follicular lymphoma This disclosure provides a method for using the expression levels (e.g., mRNA level or protein level) of specific biomarkers to identify subjects having a subtype of follicular lymphoma (FL), to selectively treat the subtype of FL, to identify subjects likely to be responsive to FL treatment, and to predict the responsiveness of subjects to FL treatment. In certain embodiments, the subtype of FL is activated / memory B cell-like (ABC / MEM-like) FL. In certain embodiments, the subtype of FL is germinal center B cell-like (GCB-like) FL.

[0095] In one embodiment, the method provided herein is for identifying a subject as having ABC / MEM-like FL, comprising: (a) determining the gene expression level of at least one biomarker in a sample from the subject; (b) determining a composite score based on the gene expression level of at least one biomarker; and (c) identifying the subject as having ABC / MEM-like FL based on the composite score. In certain embodiments, the method further comprises treating the subject with an ABC / MEM-like FL treatment (e.g., an ABC / MEM-like FL treatment disclosed in Section 5.3).

[0096] In another embodiment, the foregoing provides a method for selectively treating a subject having FL, comprising: (a) determining the gene expression level of at least one biomarker in a sample from the subject; (b) determining a composite score based on the gene expression level of at least one biomarker; (c) identifying the subject as having ABC / MEM-like FL based on the composite score; and (d) administering an ABC / MEM-like FL treatment (e.g., the ABC / MEM-like FL treatment disclosed in Section 5.3) to the subject identified as having ABC / MEM-like FL.

[0097] In another embodiment, the foregoing provides a method for identifying a subject likely to be responsive to ABC / MEM-like FL treatment or for predicting the responsiveness of a subject to ABC / MEM-like FL treatment, comprising: (a) determining the gene expression level of at least one biomarker in a sample of the subject; (b) determining a composite score based on the gene expression level of at least one biomarker; and (c) identifying or predicting, based on the composite score, that the subject is likely to be responsive to ABC / MEM-like FL treatment. In certain embodiments, the method further comprises administering ABC / MEM-like FL treatment to a subject likely to be responsive to ABC / MEM-like FL treatment.

[0098] In certain embodiments, the ABC / MEM-like therapy disclosed herein comprises a therapeutically effective amount of an immunomodulatory agent (IMiD®). In certain embodiments, the ABC / MEM-like therapy disclosed herein comprises a therapeutically effective amount of a cereblon E3 ligase-modulating compound. In certain embodiments, the ABC / MEM-like therapy further comprises a therapeutically effective amount of an anti-CD20 antibody. In certain embodiments, the ABC / MEM-like therapy comprises a combination of a therapeutically effective amount of IMiD® and / or a cereblon E3 ligase-modulating compound and an anti-CD20 antibody. Further description of the ABC / MEM-like therapy disclosed herein is provided in Section 5.3.

[0099] In another embodiment, the method provided herein is for identifying a subject to have GCB-like FL, comprising: (a) determining the gene expression level of at least one biomarker in a sample from the subject; (b) determining a composite score based on the gene expression level of at least one biomarker; and (c) identifying the subject to have GCB-like FL based on the composite score. In certain embodiments, the method further comprises treating the subject with a GCB-like FL treatment (e.g., a GCB-like FL treatment disclosed in Section 5.3).

[0100] In another embodiment, the foregoing provides a method for selectively treating a subject having FL, comprising: (a) determining the gene expression level of at least one biomarker in a sample; (b) determining a composite score based on the gene expression level of at least one biomarker; (c) identifying the subject as having GCB-like FL based on the composite score; and (d) administering a GCB-like FL treatment (e.g., the GCB-like FL treatment disclosed in Section 5.3) to the subject identified as having GCB-like FL.

[0101] In another embodiment, the foregoing provides a method for identifying a subject likely to be responsive to GCB-like FL treatment or for predicting the responsiveness of a subject to GCB-like FL treatment, comprising: (a) determining the gene expression level of at least one biomarker in a sample of the subject; (b) determining a composite score based on the gene expression level of at least one biomarker; and (c) identifying or predicting, based on the composite score, that the subject is likely to be responsive to GCB-like FL treatment. In certain embodiments, the method further comprises administering GCB-like FL treatment to a subject likely to be responsive to GCB-like FL treatment.

[0102] In certain embodiments, the GCB-like therapy disclosed herein comprises a therapeutically effective amount of an immunomodulatory agent (IMiD®), an anti-CD20 antibody, a chemotherapeutic agent, or a combination thereof. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective amount of IMiD® and an anti-CD20 antibody. In certain embodiments, the GCB-like therapy disclosed herein comprises a therapeutically effective amount of a cereblon E3 ligase modifier, an anti-CD20 antibody, a chemotherapeutic agent, or a combination thereof. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective amount of a cereblon E3 ligase modifier and an anti-CD20 antibody. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective amount of an anti-CD20 antibody and at least one chemotherapeutic agent. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective amount of an anti-CD20 antibody and two or more (e.g., 2, 3, 4, or 5) chemotherapeutic agents. In certain embodiments, the GCB-like therapy disclosed herein further comprises a steroid hormone. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective dose of anti-CD20 antibody, at least one chemotherapeutic agent, and a steroid hormone. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective dose of anti-CD20 antibody, two or more (e.g., 2, 3, 4, or 5) chemotherapeutic agents, and a steroid hormone. A further description of the GCB-like therapies disclosed herein is provided in Section 5.3.

[0103] In certain embodiments, the methods disclosed herein further include obtaining a sample from the subject.

[0104] In certain embodiments, the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1.

[0105] In certain embodiments, the subject is an object having FL or an object suspected of having FL. In certain embodiments, the subject is a human subject.

[0106] In certain embodiments, the sample is a peripheral blood sample. In certain embodiments, the sample is a tissue sample. In certain embodiments, the sample is a tumor biopsy. In certain embodiments, the sample disclosed herein includes FL cells. A more detailed description of the sample (e.g., biological sample) is provided in Section 5.5 below.

[0107] In certain embodiments, the composite score is a gene signature that includes a set of genes found to be increased or decreased in subjects having one subtype of FL (e.g., ABC / MEM-like FL) compared to subjects having another subtype of FL (e.g., GCB-like FL). In certain embodiments, the composite score indicates subjects having ABC / MEM-like FL. In certain embodiments, the composite score indicates subjects having GCB-like FL.

[0108] In certain embodiments, the composite score is determined based on the gene expression level of one or more biomarkers selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1.

[0109] In certain embodiments, the composite score is determined based on the gene expression levels of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 biomarkers selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1.

[0110] In certain embodiments, the composite score is calculated as a weighted sum of the gene expression levels of one or more biomarkers selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1.

[0111] In a particular embodiment, the composite score is calculated as follows: (TTC28 gene expression level × TTC28 weight) + (FOXP1 gene expression level × FOXP1 weight) + (DOPEY2 gene expression level × DOPEY2 weight) + (IQSEC1 gene expression level × IQSEC1 weight) + (PTPRJ gene expression level × PTPRJ weight) + (SLA gene expression level × SLA weight) + (CXXC5 gene expression level × CXXC5 weight) + (PDE4B gene expression level × PDE4B weight) + (TCF4 gene expression level × TCF4 weight) + (MPEG1 gene expression level × MPEG1 weight) (weight) + (KIAA1211 gene expression level × KIAA1211 weight) + (SCPEP1 gene expression level × SCPEP1 weight) + (RASL11A gene expression level × RASL11A weight) + (LMO2 gene expression level × LMO2 weight) + (HS2ST1 gene expression level × HS2ST1 weight) + (ENPP3 gene expression level × ENPP3 weight) + (SH3RF1 gene expression level × SH3RF1 weight) + (SCIMP gene expression level × SCIMP weight) + (CCDC138 gene expression level × CCDC138 weight) + (SHCBP1 gene expression level × SHCBP1 weight).

[0112] In a particular embodiment, the composite score is calculated as follows: (Gene expression level of TTC28 × Weight of TTC28) + (Gene expression level of FOXP1 × Weight of FOXP1) + (Gene expression level of DOPEY2 × Weight of DOPEY2) + (Gene expression level of IQSEC1 × Weight of IQSEC1) + (Gene expression level of PTPRJ × Weight of PTPRJ) + (Gene expression level of SLA × Weight of SLA) + (Gene expression level of CXXC5 × Weight of CXXC5) + (Gene expression level of PDE4B × Weight of PDE4B) + (Gene expression level of TCF4 × Weight of TCF4) + (Gene expression level of MPEG1 × Weight of MPEG1).

[0113] In a particular embodiment, the composite score is calculated as follows: (gene expression level of KIAA1211 × weight of KIAA1211) + (gene expression level of SCPEP1 × weight of SCPEP1) + (gene expression level of RASL11A × weight of RASL11A) + (gene expression level of LMO2 × weight of LMO2) + (gene expression level of HS2ST1 × weight of HS2ST1) + (gene expression level of ENPP3 × weight of ENPP3) + (gene expression level of SH3RF1 × weight of SH3RF1) + (gene expression level of SCIMP × weight of SCIMP) + (gene expression level of CCDC138 × weight of CCDC138) + (gene expression level of SHCBP1 × weight of SHCBP1).

[0114] In certain embodiments, the weighted values ​​of the gene expression levels of one or more biomarkers selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, and MPEG1 are less than zero. In certain embodiments, the weighted values ​​of the gene expression levels of one or more biomarkers selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, and MPEG1 are approximately -20 to approximately -10. In certain embodiments, the weighted values ​​of the gene expression levels of one or more biomarkers selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, and MPEG1 are approximately -19 to -12, approximately -19 to -13, approximately -18 to -12, or approximately -18 to -13.

[0115] In certain embodiments, the weighted value of the gene expression levels of one or more biomarkers selected from the group consisting of KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1 is greater than zero. In certain embodiments, the weighted value of the gene expression levels of one or more biomarkers selected from the group consisting of KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1 is about 10 to about 20. In certain embodiments, the weighted value of the gene expression levels of one or more biomarkers selected from the group consisting of KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1 is about 15 to about 19 or about 15 to about 18.

[0116] In a specific embodiment, the composite score is calculated as follows: (TTC28 gene expression level × -12.90235) + (FOXP1 gene expression level × -17.20497) + (DOPEY2 gene expression level × -14.08426) + (IQSEC1 gene expression level × -14.14635) + (PTPRJ gene expression level × -15.78924) + (SLA gene expression level × -13.44714) + (CXXC5 gene expression level × -13.21572) + (PDE4B gene expression level × -14.31872) + (TCF4 gene expression level × -18.17919) + (MPEG1 gene expression level (Bell × -16.21973) + (KIAA1211 gene expression level × 15.81861) + (SCPEP1 gene expression level × 15.97033) + (RASL11A gene expression level × 17.50829) + (LMO2 gene expression level × 17.18333) + (HS2ST1 gene expression level × 15.22055) + (ENPP3 gene expression level × 15.22908) + (SH3RF1 gene expression level × 15.60008) + (SCIMP gene expression level × 18.07827) + (CCDC138 gene expression level × 15.04494) + (SHCBP1 gene expression level × 15.84456).

[0117] In a specific embodiment, the composite score is calculated as follows: (TTC28 gene expression level × -12.9) + (FOXP1 gene expression level × -17.2) + (DOPEY2 gene expression level × -14.1) + (IQSEC1 gene expression level × -14.1) + (PTPRJ gene expression level × -15.8) + (SLA gene expression level × -13.4) + (CXXC5 gene expression level × -13.2) + (PDE4B gene expression level × -14.3) + (TCF4 gene expression level × -18.2) + (MPEG1 gene expression level) (Genetic expression level × -16.2) + (Genetic expression level of KIAA1211 × 15.8) + (Genetic expression level of SCPEP1 × 16.0) + (Genetic expression level of RASL11A × 17.5) + (Genetic expression level of LMO2 × 17.2) + (Genetic expression level of HS2ST1 × 15.2) + (Genetic expression level of ENPP3 × 15.2) + (Genetic expression level of SH3RF1 × 15.6) + (Genetic expression level of SCIMP × 18.1) + (Genetic expression level of CCDC138 × 15.0) + (Genetic expression level of SHCBP1 × 15.8).

[0118] In a particular embodiment, the composite score is calculated as follows: (TTC28 gene expression level × -12.90235) + (FOXP1 gene expression level × -17.20497) + (DOPEY2 gene expression level × -14.08426) + (IQSEC1 gene expression level × -14.14635) + (PTPRJ gene expression level × -15.78924) + (SLA gene expression level × -13.44714) + (CXXC5 gene expression level × -13.21572) + (PDE4B gene expression level × -14.31872) + (TCF4 gene expression level × -18.17919) + (MPEG1 gene expression level × -16.21973). In a particular embodiment, the composite score is calculated as follows: (Genetic expression level of KIAA1211 × 15.81861) + (Genetic expression level of SCPEP1 × 15.97033) + (Genetic expression level of RASL11A × 17.50829) + (Genetic expression level of LMO2 × 17.18333) + (Genetic expression level of HS2ST1 × 15.22055) + (Genetic expression level of ENPP3 × 15.22908) + (Genetic expression level of SH3RF1 × 15.60008) + (Genetic expression level of SCIMP × 18.07827) + (Genetic expression level of CCDC138 × 15.04494) + (Genetic expression level of SHCBP1 × 15.84456).

[0119] In a particular embodiment, the composite score is calculated as follows: (TTC28 gene expression level × -12.9) + (FOXP1 gene expression level × -17.2) + (DOPEY2 gene expression level × -14.1) + (IQSEC1 gene expression level × -14.1) + (PTPRJ gene expression level × -15.8) + (SLA gene expression level × -13.4) + (CXXC5 gene expression level × -13.2) + (PDE4B gene expression level × -14.3) + (TCF4 gene expression level × -18.2) + (MPEG1 gene expression level × -16.2). In a particular embodiment, the composite score is calculated as follows: (gene expression level of KIAA1211 × 15.8) + (gene expression level of SCPEP1 × 16.0) + (gene expression level of RASL11A × 17.5) + (gene expression level of LMO2 × 17.2) + (gene expression level of HS2ST1 × 15.2) + (gene expression level of ENPP3 × 15.2) + (gene expression level of SH3RF1 × 15.6) + (gene expression level of SCIMP × 18.1) + (gene expression level of CCDC138 × 15.0) + (gene expression level of SHCBP1 × 15.8).

[0120] In certain embodiments, if the composite score is lower than a predetermined value, the subject is identified as having ABC / MEM-like FL, or is identified or predicted to be likely to respond to treatment for ABC / MEM-like FL. In certain embodiments, if the composite score is higher than a predetermined value, the subject is identified as having GCB-like FL, or is identified or predicted to be likely to respond to treatment for GCB-like FL. In certain embodiments, the predetermined value is zero or approximately zero.

[0121] In certain embodiments, if the composite score is lower than the reference score, the subject is identified as having ABC / MEM-like FL, or is identified or predicted to be likely to respond to treatment for ABC / MEM-like FL. In certain embodiments, if the composite score is higher than the reference score, the subject is identified as having GCB-like FL, or is identified or predicted to be likely to respond to treatment for GCB-like FL. In certain embodiments, the reference score is derived from a healthy subject or a population of healthy subjects. In certain embodiments, the reference score is calculated in the same manner as the composite score. In certain embodiments, the reference score is zero or approximately zero.

[0122] In another embodiment, the method provided herein identifies a subject as having ABC / MEM-like FL, comprising (a) determining the protein expression levels of FOXP1, LMO2, CD22, and MUM1 in a sample from the subject; and (b) identifying the subject as having ABC / MEM-like FL based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1. In certain embodiments, the method further comprises treating the subject with an ABC / MEM-like FL treatment (e.g., an ABC / MEM-like FL treatment disclosed in Section 5.3).

[0123] In another embodiment, the Specified Provision is a method for selectively treating subjects having FL, comprising: (a) determining the protein expression levels of FOXP1, LMO2, CD22 and MUM1 in a sample of the subject; (b) identifying the subject as having ABC / MEM-like FL based on the protein expression levels of FOXP1, LMO2, CD22 and MUM1; and (c) administering ABC / MEM-like FL treatment (e.g., ABC / MEM-like FL treatment as disclosed in Section 5.3) to the subject identified as having ABC / MEM-like FL.

[0124] In another embodiment, the Specified Method for identifying a subject likely to be responsive to ABC / MEM-like FL treatment (e.g., ABC / MEM-like FL treatment as disclosed in Section 5.3) or for predicting the responsiveness of a subject to ABC / MEM-like FL treatment, comprising: (a) determining the protein expression levels of FOXP1, LMO2, CD22, and MUM1 in a sample of the subject; and (b) identifying or predicting, based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1, that the subject is likely to be responsive to ABC / MEM-like FL treatment. In certain embodiments, the Method further comprises administering ABC / MEM-like FL treatment to a subject likely to be responsive to ABC / MEM-like FL treatment.

[0125] In certain embodiments, the ABC / MEM-like therapy disclosed herein comprises a therapeutically effective amount of an immunomodulatory agent (IMiD®). In certain embodiments, the ABC / MEM-like therapy disclosed herein comprises a therapeutically effective amount of a cereblon E3 ligase-modulating compound. In certain embodiments, the ABC / MEM-like therapy further comprises a therapeutically effective amount of an anti-CD20 antibody. In certain embodiments, the ABC / MEM-like therapy comprises a combination of a therapeutically effective amount of IMiD® and / or a cereblon E3 ligase-modulating compound and an anti-CD20 antibody. Further description of the ABC / MEM-like therapy disclosed herein is provided in Section 5.3.

[0126] In another embodiment, the method provided herein identifies a subject as having GCB-like FL, comprising: (a) determining the protein expression levels of FOXP1, LMO2, CD22, and MUM1 in a sample from the subject; and (b) identifying the subject as having GCB-like FL based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1. In certain embodiments, the method further comprises treating the subject with a GCB-like FL treatment (e.g., a GCB-like FL treatment disclosed in Section 5.3).

[0127] In another embodiment, the foregoing provides a method for selectively treating subjects having FL, comprising: (a) determining the protein expression levels of FOXP1, LMO2, CD22 and MUM1 in a sample; (b) identifying the subject as having GCB-like FL based on the protein expression levels of FOXP1, LMO2, CD22 and MUM1; and (c) administering a GCB-like FL treatment (e.g., the GCB-like FL treatment disclosed in Section 5.3) to the subject identified as having GCB-like FL.

[0128] In another embodiment, the foregoing provides a method for identifying a subject likely to be responsive to GCB-like FL treatment (e.g., GCB-like FL treatment as disclosed in Section 5.3) or for predicting the responsiveness of a subject to GCB-like FL treatment, comprising: (a) determining the protein expression levels of FOXP1, LMO2, CD22 and MUM1 in a sample of the subject; and (b) identifying or predicting, based on the protein expression levels of FOXP1, LMO2, CD22 and MUM1, that the subject is likely to be responsive to GCB-like FL treatment. In certain embodiments, the method further comprises administering GCB-like FL treatment to a subject likely to be responsive to GCB-like FL treatment.

[0129] In certain embodiments, the GCB-like therapy disclosed herein comprises a therapeutically effective amount of an immunomodulatory agent (IMiD®), an anti-CD20 antibody, a chemotherapeutic agent, or a combination thereof. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective amount of IMiD® and an anti-CD20 antibody. In certain embodiments, the GCB-like therapy disclosed herein comprises a therapeutically effective amount of a cereblon E3 ligase modifier, an anti-CD20 antibody, a chemotherapeutic agent, or a combination thereof. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective amount of a cereblon E3 ligase modifier and an anti-CD20 antibody. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective amount of an anti-CD20 antibody and at least one chemotherapeutic agent. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective amount of an anti-CD20 antibody and two or more (e.g., 2, 3, 4, or 5) chemotherapeutic agents. In certain embodiments, the GCB-like therapy disclosed herein further comprises a steroid hormone. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective dose of anti-CD20 antibody, at least one chemotherapeutic agent, and a steroid hormone. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective dose of anti-CD20 antibody, two or more (e.g., 2, 3, 4, or 5) chemotherapeutic agents, and a steroid hormone.

[0130] In certain embodiments, the methods disclosed herein further include obtaining a sample from the subject.

[0131] In certain embodiments, the expression levels of FOXP1, LMO2, CD22, and MUM1 are the protein levels of FOXP1, LMO2, CD22, and MUM1. In certain embodiments, the protein levels of FOXP1, LMO2, CD22, and MUM1 are measured using immunohistochemistry (IHC). In some embodiments, the protein levels of FOXP1, LMO2, CD22, and MUM1 are measured using multiplex ion beam imaging (MIBI). In some embodiments, the protein levels of FOXP1, LMO2, CD22, and MUM1 are measured using imaging mass cytometry (IMC). Additional methods for measuring the protein levels of FOXP1, LMO2, and MUM1 are disclosed in Section 5.6.

[0132] In certain embodiments, the expression level of a protein is determined based on whether the cell is positive or negative for that protein. In certain embodiments, the expression levels of FOXP1, LMO2, CD22, and MUM1 are determined based on whether the cell is positive or negative for FOXP1, LMO2, CD22, and MUM1. In certain embodiments, a cell is positive for FOXP1, LMO2, CD22, or MUM1 if there is strong or moderate staining of the respective protein in the cell. In certain embodiments, a cell is negative for FOXP1, LMO2, CD22, or MUM1 if there is weak or no staining of the respective protein in the cell.

[0133] In certain embodiments, if the FOXP1 protein expression level is strong or moderate and the LMO2 protein expression level is weak or negative, the subject is identified as having ABC / MEM-like FL or is identified or predicted to be likely to respond to treatment for ABC / MEM-like FL. In certain embodiments, if the FOXP1 protein expression level differs significantly from the LMO2 protein expression level, the percentage of FOXP1-positive cells in the sample is greater than approximately 50%, the percentage of LMO2-positive cells in the sample is less than approximately 50%, and the difference between the percentage of FOXP1-positive cells and the percentage of LMO2-positive cells in the sample is greater than approximately 20%, the subject is identified as having ABC / MEM-like FL or is identified or predicted to be likely to respond to treatment for ABC / MEM-like FL. In certain embodiments, if the protein expression level of FOXP1 is close to (equivalently strong, moderate, or weak) that of LMO2, or otherwise of no informational value, and the protein expression level of CD22 is weak, the subject is identified as having ABC / MEM-like FL, or is identified or predicted to be likely to be responsive to treatment for ABC / MEM-like FL. In certain embodiments, if the protein expression level of FOXP1 is close to (equivalently strong, moderate, or weak) that of LMO2, or otherwise of no informational value, and the protein expression level of CD22 is moderate or otherwise of no informational value, and the percentage of MUM1-positive cells in the sample is greater than approximately 15%, the subject is identified as having ABC / MEM-like FL. In certain embodiments, if the percentage of CD22-positive cells in the sample is less than approximately 20%, the protein expression level of CD22 is weak. In certain embodiments, if the percentage of CD22-positive cells in the sample is approximately 20% to 80%, the CD22 protein expression level is moderate or otherwise of no informational value.In certain embodiments, the protein expression level of FOXP1 is either similar to (equivalently strong, moderate, or weak) or otherwise of no informational value if the difference between the percentage of FOXP1-positive cells in the sample and the percentage of LMO2-positive cells in the sample is less than approximately 20%.

[0134] In certain embodiments, (i) the percentage of FOXP1-positive cells in the sample is greater than approximately 50%, and the percentage of LMO2-positive cells in the sample is less than approximately 50%, and the difference between the percentage of FOXP1-positive cells and the percentage of LMO2-positive cells in the sample is about 20% or more; (ii) the difference between the percentage of FOXP1-positive cells and the percentage of LMO2-positive cells in the sample is less than approximately 20%, and the percentage of CD22-positive cells in the sample If the stage is less than approximately 20%, or (iii) if the difference between the percentage of FOXP1-positive cells in the sample and the percentage of LMO2-positive cells in the sample is less than approximately 20%, and the percentage of CD22-positive cells in the sample is between approximately 20% and 80%, and the percentage of MUM1-positive cells in the sample is greater than approximately 15%, then the subject is identified as having ABC / MEM-like FL, or is identified or predicted to be likely to respond to treatment for ABC / MEM-like FL.

[0135] In certain embodiments, if the protein expression level of FOXP1 is weak or negative and the protein expression level of LMO2 is strong or moderate, the subject is identified as having GCB-like FL or is identified or predicted to be likely to respond to treatment for GCB-like FL. In certain embodiments, if the protein expression level of FOXP1 is significantly different from that of LMO2, the percentage of FOXP1-positive cells in the sample is less than approximately 50%, the percentage of LMO2-positive cells in the sample is greater than approximately 50%, and the difference between the percentage of FOXP1-positive cells and the percentage of LMO2-positive cells in the sample is approximately 20% or more, the subject is identified as having GCB-like FL or is identified or predicted to be likely to respond to treatment for GCB-like FL. In certain embodiments, if the LMO2 protein expression level is close to (equivalently strong, moderate, or weak) that of FOXP1 protein expression level, or otherwise of no informational value, and the CD22 protein expression level is strong, the subject is identified as having GCB-like FL, or is identified or predicted to be likely to be responsive to treatment for GCB-like FL. In certain embodiments, if the LMO2 protein expression level is close to (equivalently strong, moderate, or weak) that of FOXP1 protein expression level, or otherwise of no informational value, and the CD22 protein expression level is moderate or otherwise of no informational value, and the percentage of MUM1-positive cells in the sample is less than approximately 10%, the subject is identified as having GCB-like FL, or is identified or predicted to be likely to be responsive to treatment for GCB-like FL. In certain embodiments, the LMO2 protein expression level is similar to (equally strong, moderate, or weak) or otherwise of no informational value if the difference between the percentage of FOXP1-positive cells in the sample and the percentage of LMO2-positive cells in the sample is less than approximately 20%. In certain embodiments, the CD22 protein expression level is strong if the percentage of CD22-positive cells in the sample is greater than approximately 80%.In certain embodiments, if the percentage of CD22-positive cells in the sample is approximately 20% to 80%, the CD22 protein expression level is moderate or otherwise of no informational value.

[0136] In certain embodiments, (i) the percentage of LMO2-positive cells in the sample is greater than approximately 50%, and the percentage of FOXP1-positive cells in the sample is less than approximately 50%, and the difference between the percentage of LMO2-positive cells in the sample and the percentage of FOXP1-positive cells in the sample is about 20% or more; (ii) the difference between the percentage of FOXP1-positive cells in the sample and the percentage of LMO2-positive cells in the sample is less than approximately 20%, and the CD22 cells in the sample are If the percentage is greater than approximately 80%, or (iii) if the difference between the percentage of FOXP1-positive cells in the sample and the percentage of LMO2-positive cells in the sample is less than approximately 20%, the percentage of CD22-positive cells in the sample is between approximately 20% and approximately 80%, and the percentage of MUM1-positive cells in the sample is less than approximately 10%, then the subject is identified as having GCB-like FL, or is identified or predicted to be highly responsive to treatment for GCB-like FL.

[0137] In certain embodiments, strong, moderate, weak, or negative protein levels are determined by staining intensity measured by immunohistochemistry. Those skilled in the art will understand how strong, moderate, weak, and negative protein levels are determined using methods known in the art (e.g., H-scores, Allred scores, and immunoreactivity scores).

[0138] 5.3 ABC / MEM-like FL treatment and GCB-like FL treatment In certain embodiments, the ABC / MEM-like therapy disclosed herein comprises a therapeutically effective amount of an immunomodulator (IMiD®). In certain embodiments, the ABC / MEM-like therapy disclosed herein comprises a therapeutically effective amount of a cereblon E3 ligase-modifying compound. In certain embodiments, the ABC / MEM-like therapy further comprises a therapeutically effective amount of an anti-CD20 antibody. In certain embodiments, the ABC / MEM-like therapy comprises a combination of a therapeutically effective amount of IMiD® and / or a cereblon E3 ligase-modifying compound and an anti-CD20 antibody. In certain embodiments, IMiD® and / or a cereblon E3 ligase-modifying compound is lenalidomide, pomalidomide, thalidomide, iverdamide and formula (I) [ka] The compounds are selected from the group consisting of the following: compounds and their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions and pharmaceutically acceptable salts. In certain embodiments, IMiD® is selected from the group consisting of lenalidomide, pomalidomide and thalidomide and their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions and pharmaceutically acceptable salts. In certain embodiments, the cerebron E3 ligase modulating compound is iverdamide and formula (I) [ka] The compounds are selected from the group consisting of the following: compounds and their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions and pharmaceutically acceptable salts. In certain embodiments, the cerebron E3 ligase modulating compounds are lenalidomide, pomalidomide, thalidomide, iverdomide and formula (I) [ka] The compounds are selected from the group consisting of the following: compounds, their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions, and pharmaceutically acceptable salts.

[0139] In certain embodiments, the ABC / MEM-like therapies disclosed herein comprise a therapeutically effective amount of rituximab and lenalidomide or its enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions, or pharmaceutically acceptable salts.

[0140] In certain embodiments, the ABC / MEM-like therapy disclosed herein involves a therapeutically effective dose of rituximab and formula (I) [ka] This includes compounds thereof, their enantiomers, mixtures of enantiomers, tautomers, isotope substitutions, or pharmaceutically acceptable salts.

[0141] In certain embodiments, the GCB-like therapy disclosed herein comprises a therapeutically effective dose of IMiD®, a cereblon E3 ligase modifier, an anti-CD20 antibody, a chemotherapeutic agent, or a combination thereof. In certain embodiments, the GCB-like therapy comprises a combination of IMiD® and an anti-CD20 antibody. In certain embodiments, the GCB-like therapy comprises a combination of a cereblon E3 ligase modifier and an anti-CD20 antibody. In certain embodiments, the GCB-like therapy comprises a combination of an anti-CD20 antibody and a chemotherapeutic agent. In certain embodiments, the GCB-like therapy comprises a combination of an anti-CD20 antibody and two or more chemotherapeutic agents (e.g., two, three, four, five or more chemotherapeutic agents). In certain embodiments, the GCB-like therapy comprises a combination of an anti-CD20 antibody and three chemotherapeutic agents. In certain embodiments, the GCB-like therapy disclosed herein further comprises a steroid hormone. In certain embodiments, the GCB-like therapy comprises a therapeutically effective dose of an anti-CD20 antibody, at least one chemotherapeutic agent, and a steroid hormone. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective dose of an anti-CD20 antibody, two or more chemotherapeutic agents (e.g., two, three, four, five, or more chemotherapeutic agents), and a steroid hormone. In certain embodiments, the GCB-like therapy comprises a combination of an anti-CD20 antibody, three chemotherapeutic agents, and a steroid hormone.

[0142] In certain embodiments, the GCB-like therapies disclosed herein comprise a therapeutically effective amount of rituximab and lenalidomide or its enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions, or pharmaceutically acceptable salts. In certain embodiments, the GCB-like therapy comprises a combination of a cereblon E3 ligase modifier and rituximab. In certain embodiments, the IMiD® and / or cereblon E3 ligase modifiers disclosed herein comprise lenalidomide, pomalidomide, thalidomide, iverdamide, and formula (I) [ka] The compounds are selected from the group consisting of the following: compounds or their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions and pharmaceutically acceptable salts. In certain embodiments, IMiD® is selected from the group consisting of lenalidomide, pomalidomide and thalidomide and their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions and pharmaceutically acceptable salts. In certain embodiments, the cerebron E3 ligase modulating compound is iverdamide and formula (I) [ka] The compounds are selected from the group consisting of the following: compounds and their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions and pharmaceutically acceptable salts. In certain embodiments, the cerebron E3 ligase modulating compounds are lenalidomide, pomalidomide, thalidomide, iverdomide and formula (I) [ka] The compounds are selected from the group consisting of the following: compounds, their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions, and pharmaceutically acceptable salts.

[0143] In certain embodiments, the GCB-like treatment disclosed herein involves a therapeutically effective dose of rituximab and formula (I) [ka] This includes compounds thereof, their enantiomers, mixtures of enantiomers, tautomers, isotope substitutions, or pharmaceutically acceptable salts.

[0144] In certain embodiments, the GCB-like therapy disclosed herein comprises a therapeutically effective dose of rituximab, cyclophosphamide, doxorubicin hydrochloride, and vincristine sulfate.

[0145] In certain embodiments, the GCB-like therapy comprises a combination of an anti-CD20 antibody, a chemotherapeutic agent, and a steroid hormone. In certain embodiments, the steroid hormone is prednisone. In certain embodiments, the GCB-like therapy disclosed herein comprises a therapeutically effective dose of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone.

[0146] Therapeutic agents in combination therapy may be administered simultaneously or as separate courses of treatment. As used herein, the term “combined” does not limit the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a patient with a disease or disorder. The administration of a second therapy provided herein to a patient may be carried out simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration used for a particular activator will depend on the activator itself (e.g., whether it can be administered orally without being broken down before entering the bloodstream).

[0147] In certain embodiments, the IMiD® compounds disclosed herein comprise a group of compounds that may be useful in treating several types of human diseases, including certain cancers. As used herein and unless otherwise indicated, the term “immunomodulatory compound” may encompass cereblon (CRBN) modulators. In certain embodiments, a CRBN modulator is a drug that can directly or indirectly modulate at least one of the biological activities of CRBN. In certain embodiments, a CRBN modulator is a drug that can physically bind to CRBN. In other embodiments, a CRBN modulator does not directly bind to CRBN but can exert its effects in other ways through the CRBN-mediated pathway. CRBN, a component of the DDB1-CUL4a-Roc1 ubiquitin ligase complex, has been identified as a target for certain immunomodulatory compounds, such as thalidomide, lenalidomide, and pomalidomide. It is thought that CRBN mediates its antiproliferative effect in multiple myeloma (MM) cells through interaction with certain immunomodulatory compounds (Lopez-Girona et al., Leukemia 2012; Zhu et al., Blood 2011, 118, Abstract 127). CRBN is encoded by a 25kb gene on chromosome 6, consisting of 11 exons and 10 introns. Therefore, alternative splicing can potentially give rise to multiple functional proteins and protein variants with different structural configurations and functional activities from a single gene. Truncate proteins lacking interaction domains or critically important functional amino acid residues can produce non-functional or abnormal CRBN proteins, which can interfere with the function of the full-length CRBN protein and reduce or alter the therapeutic activity of therapeutic compounds that exert their activity through their interaction with the full-length CRBN protein. The protein cereblon (CRBN) has at least two isoforms, each with lengths of 442 and 441 amino acids, and CRBN is conserved from plants to humans. In humans, the CRBN gene has been identified as a candidate gene for autosomal recessive non-syndromic intellectual disability (ARNSMR).See Higgins, J.J et al., Neurology, 2004, 63:1927-1931. CRBN was initially characterized as a novel RGS-containing protein that interacts with calcium-activated potassium channel protein (SLO1) in rat brain, but was later shown to interact with voltage-gated chloride channel (CIC-2) in the retina along with AMPK1 and DDB1. See Jo, S. et al., J. Neurochem, 2005, 94:1212-1224, Hohberger B. et al., FEBS Lett, 2009, 583:633-637, Angers S. et al., Nature, 2006, 443:590-593. DDB1 was initially identified as a nucleotide excision repair protein associated with damaged DNA-binding protein 2 (DDB2). Its deficiency causes repair defects in patients with xeroderma pigmentosum complementarity group E (XPE). DDB1 also appears to function as a component of several distinct DCX (DDB1-CUL4-X box)E3 ubiquitin-protein ligase complexes that mediate the ubiquitination and subsequent proteasomal degradation of target proteins. CRBNs have also been identified as targets for the development of therapeutic agents for diseases of the cerebral cortex. See International Publication No. 2010 / 137547 A1. In certain embodiments, the beneficial effects of certain therapeutic compounds provided herein require binding to CRBN or one or more CRBN substrates. In certain embodiments, the compounds provided herein for the treatment of CFS can induce a conformational change in CRBN. In certain embodiments, the use of therapeutic compounds provided herein results in a distinct conformational change of the CRBN surface or other alteration of its properties, resulting in a distinct phenotypic response.

[0148] In certain embodiments, the compounds disclosed herein are cereblon E3 ligase modulating compounds. In certain embodiments, the cereblon E3 ligase modulating compounds are agents that can directly or indirectly modulate at least one of the biological activities of cereblon E3 ligase. In certain embodiments, the cereblon E3 ligase modulating compound is IMiD®. In certain embodiments, IMiD® is selected from the group consisting of lenalidomide, pomalidomide and thalidomide and their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions and pharmaceutically acceptable salts. In certain embodiments, the cereblon E3 ligase modulating compound is iverdamide and formula (I) [ka] The compounds are selected from the group consisting of the following: compounds and their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions and pharmaceutically acceptable salts. In certain embodiments, the cerebron E3 ligase modulating compounds are lenalidomide, pomalidomide, thalidomide, iverdomide and formula (I) [ka] The compounds are selected from the group consisting of the following: compounds, their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions, and pharmaceutically acceptable salts.

[0149] In certain embodiments, the cereblon E3 ligase modulating compound is iverdomide (Lopez-Girona et al., Leukemia volume 26, pages 2326-2335 (2012), Bjorklund et al., Leukemia. 2020; 34(4): 1197-1201) or its enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions, or pharmaceutically acceptable salts.

[0150] In a particular embodiment, the cereblon E3 ligase modulating compound is (S)-2-(2,6-dioxopiperidine-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidine-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione (compound 1): [ka] or its tautomers, isotope substitutions, or pharmaceutically acceptable salts.

[0151] In certain embodiments, the cereblon E3 ligase modulating compound is (R)-2-(2,6-dioxopiperidine-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidine-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione (compound 2): [ka] or its tautomers, isotope substitutions, or pharmaceutically acceptable salts.

[0152] In a particular embodiment, the cereblon E3 ligase modulating compound is a mixture of (S)-2-(2,6-dioxopiperidine-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidine-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione and (R)-2-(2,6-dioxopiperidine-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidine-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione (compound 3): [ka] or include enantiomers thereof, mixtures of enantiomers, tautomers, isotopic substitutions, or pharmaceutically acceptable salts thereof.

[0153] In certain embodiments, cereblon E3 ligase modulo compounds or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, such as any of the compounds described in this section, can be administered to a subject orally, topically, or parenterally in conventional forms of preparations, such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations use conventional organic or inorganic additives, for example, excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), lubricants (e.g., It can be prepared by commonly used methods using magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), flavoring agents (e.g., citric acid, menthol, glycine or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben or propylparaben), stabilizers (e.g., citric acid, sodium citrate or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolicron or aluminum stearate), dispersants (e.g., hydroxypropyl methylcellulose), diluents (e.g., water), and base waxes (e.g., cocoa butter, white petrolatum or polyethylene glycol). The effective amount of the compound in the pharmaceutical composition may be at a level that produces the desired effect, and in both oral and parenteral administration, the unit dose is approximately 0.001 mg / kg to approximately 1 mg / kg of the subject's body weight.

[0154] In certain embodiments, cereblon E3 ligase modulating compounds or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof may be prepared by methods known to those skilled in the art, for example, by following the procedures described in U.S. Patent No. 8,518,972 B2 or U.S. Patent Application No. 16 / 390,815, which are incorporated herein by reference in whole, respectively.

[0155] In certain embodiments, the chemical properties, characteristics, and structure are all described in U.S. Patent Application No. 17 / 075,594, which is incorporated herein by reference in its entirety.

[0156] In certain embodiments, one or more additional cereblon E3 ligase-modified compounds may be used in combination with the administration of the treatment described herein to treat subjects having FL. In certain embodiments, one or more additional cereblon E3 ligase-modified compounds may be administered before, concurrently with, or after the administration of the treatment described herein. The administration of cancer treatment, such as antibodies or chemotherapy, and the administration of cereblon E3 ligase-modified compounds to a patient may be carried out simultaneously or sequentially via the same or different routes of administration. The suitability of a particular route of administration used for a particular cereblon E3 ligase-modified compound will depend on the cereblon E3 ligase-modified compound itself (e.g., whether it can be administered orally without being degraded before entering the bloodstream) and the state of lymphoma being treated (e.g., FL). The routes of administration of cereblon E3 ligase-modified compounds are known to those skilled in the art. See, for example, the Physicians' Desk Reference.

[0157] In certain embodiments, subjects having ABC / MEM-like FL are administered IMiD® and / or cereblon E3 ligase-modified compounds. In certain embodiments, subjects having ABC / MEM-like FL are administered IMiD® and / or cereblon E3 ligase-modified compounds selected from the group consisting of thalidomide, lenalidomide, pomalidomide, iverdide, and compounds of formula (I) or their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions, or pharmaceutically acceptable salts. In certain embodiments, IMiD and / or cereblon E3 ligase-modified compounds administered to subjects having ABC / MEM-like FL improve overall survival, progression-free survival (PFS), and / or failure-free survival (FFS).

[0158] As used herein, progression-free survival (PFS) refers to the time from the date of treatment to the first occurrence of disease progression, recurrence, or death from any cause. As used herein, failure-free survival (FFS) refers to the period during treatment without receiving second-line FL therapy, without recurrence-free death, and without recurrent or progressive malignancies.

[0159] In certain embodiments, subjects having GCB-like FL are administered IMiD® and / or cereblon E3 ligase modulating compounds. In certain embodiments, subjects having GCB-like FL are administered IMiD® and / or cereblon E3 ligase modulating compounds, which include thalidomide, lenalidomide, pomalidomide, iverdide, and compounds of formula (I) or their enantiomers, mixtures of enantiomers, tautomers, isotope substitutions, or pharmaceutically acceptable salts.

[0160] In the methods disclosed herein, any suitable anti-CD20 antibody may be used. In certain embodiments, the ABC / MEM-like therapy comprises an anti-CD20 antibody. In certain embodiments, the ABC / MEM-like therapy comprises an anti-CD20 antibody selected from the group consisting of rituximab, obinutuzumab, and ocrelizumab. In certain embodiments, the GCB-like therapy comprises an anti-CD20 antibody. In certain embodiments, the GCB-like therapy comprises an anti-CD20 antibody selected from the group consisting of rituximab, obinutuzumab, and ocrelizumab.

[0161] Any suitable chemotherapeutic agent may be used in this disclosure.

[0162] In certain embodiments, the chemotherapeutic agent is selected from the group consisting of cyclophosphamide, doxorubicin, vincristine, bendamustine, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin, dexamethasone or its stereoisomers, mixtures of stereoisomers, tautomers, isotope substitutions, prodrugs or pharmaceutically acceptable salts.

[0163] 5.5 Biological Samples In certain embodiments, the various methods provided herein utilize samples (e.g., biological samples) from FL patients. Patients may be male or female, and may be adults, children, or infants. Samples may be analyzed at some point during the active phase of FL or during the inactive phase of FL. In one embodiment, samples are obtained from the patient before, in parallel with, and / or after the administration of the drug described herein. In specific embodiments, samples are obtained from the patient before the administration of the drug described herein. In certain embodiments, multiple samples may be obtained from the patient.

[0164] In certain embodiments, the biological sample is a tissue biopsy. In certain embodiments, the biological sample is a tumor biopsy. In certain embodiments, the biological sample is a lymph node biopsy. In certain embodiments, the biological sample is a biopsy of an affected lymph node (e.g., a lymph node containing tumor cells). In certain embodiments, the biological sample is an excision biopsy or core needle biopsy of an affected lymph node. In certain embodiments, the tissue biopsy (e.g., a biopsy of an affected lymph node) is stored as an FFPE slide. In certain embodiments, the FFPE slide may be used for (i) RNA extraction for gene expression classification, or (ii) immunofluorescence histochemistry (IF) staining or similar imaging-based platforms such as MIBI and IMC for protein-based classification.

[0165] In certain embodiments, the sample used in the methods provided herein includes bodily fluids from the subject. Non-limiting examples of bodily fluids include blood (e.g., peripheral whole blood, peripheral blood), plasma, amniotic fluid, aqueous humor, bile, earwax, Cowper's gland fluid, bulbourethral gland fluid, chyle, ointment, female ejaculate, interstitial fluid, lymph, menstrual fluid, breast milk, mucus, pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal lubrication, vomit, water, feces, internal bodily fluids (including cerebrospinal fluid surrounding the brain and spinal cord), synovial fluid surrounding bones and joints, intracellular fluid (the fluid inside cells), and vitreous fluid (the fluid in the eyeball). In certain embodiments, the sample is a blood sample. Blood samples can be obtained using conventional techniques, for example, as described in Innis et al, editors, PCR Protocols (Academic Press, 1990). Leukocytes can be isolated from blood samples using conventional techniques or commercially available kits, such as the RosetteSep kit (Stein Cell Technologies, Vancouver, Canada). Subpopulations of leukocytes, such as mononuclear cells, B cells, T cells, monocytes, granulocytes, or lymphocytes, can be further isolated using conventional techniques, such as magnetically activated cell sorting (MACS) (Miltenyi Biotec, Auburn, California) or fluorescence-activated cell sorting (FACS) (Becton Dickinson, San Jose, California).

[0166] In certain embodiments, the blood sample is approximately 0.1 mL to 10.0 mL, approximately 0.2 mL to 7 mL, approximately 0.3 mL to 5 mL, approximately 0.4 mL to 3.5 mL, or approximately 0.5 mL to 3 mL. In another embodiment, the blood sample is approximately 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 1.5 mL, 2.0 mL, 2.5 mL, 3.0 mL, 3.5 mL, 4.0 mL, 4.5 mL, 5.0 mL, 6.0 mL, 7.0 mL, 8.0 mL, 9.0 mL, or 10.0 mL.

[0167] In certain embodiments, the sample used in this method includes a biopsy (e.g., a tumor biopsy). The biopsy may be from any organ or tissue, such as skin, liver, lung, heart, colon, kidney, bone marrow, teeth, lymph nodes, hair, spleen, brain, breast, or other organ. In specific embodiments, the sample used in the method described herein includes a tumor biopsy. Any biopsy technique known to those skilled in the art, such as open biopsy, closed biopsy, core biopsy, incision biopsy, excision biopsy, or fine-needle aspiration biopsy, can be used to isolate the sample from the subject.

[0168] In certain embodiments, the sample used in the methods provided herein is obtained from the subject before the patient receives treatment for FL. In other embodiments, the sample is obtained from the patient while the subject is receiving treatment for FL. In yet another embodiment, the sample is obtained from the patient after the patient has received treatment for FL. In various embodiments, the treatment includes administering a compound described herein (e.g., a compound of formula (I)) to the subject.

[0169] In certain embodiments, the sample used in the methods provided herein comprises a plurality of cells. Such cells can include any type of cell, such as stem cells, blood cells (e.g., peripheral blood mononuclear cells), lymphocytes, B cells, T cells, monocytes, granulocytes, immune cells or tumor cells or cancer cells. Tumor cells or cancer cells or tumor tissues such as tumor biopsies or tumor explants. T cells (T lymphocytes) include, for example, helper T cells (effector T cells or Th cells), cytotoxic T cells (CTLs), memory T cells and regulatory T cells. In one embodiment, the cells used in the methods provided herein are CD3 + T cells, detected, for example, by flow cytometry. The number of T cells used in the method can range from a single cell to about 10 9 cells. B cells (B lymphocytes) include, for example, plasma B cells, dendritic cells, memory B cells, B1 cells, B2 cells, marginal zone B cells and follicular B cells. B cells can express immunoglobulins (antibodies, B cell receptors

[0170] In certain embodiments, a given cell population can be obtained using a combination of commercially available antibodies (e.g., Quest Diagnostic (San Juan Capistrano, Calif.), Dako (Denmark)).

[0171] In certain embodiments, the sample used in the methods provided herein is diseased tissue from an FL patient. In certain embodiments, the number of cells used in the methods provided herein can range from a single cell to about 10 9 cells. In certain embodiments, the number of cells used in the methods provided herein is about 1×10 [[ID=##]] 4 cells, 5×10 4 [[ID=##]]cells, 1×10 5 cells, 5×10 5 cells, 1×10 6 cells, 5×10 6 cells, 1×10 7 cells, 5×10 7 cells, 1×10 8 cells or 5×108 It is a cell.

[0172] In certain embodiments, the number and types of cells collected from a subject can be monitored by measuring changes in morphology and cell surface markers using standard cell detection techniques such as flow cytometry, cell sorting, immunocytochemistry (e.g., staining with tissue-specific or cell marker-specific antibodies), fluorescence-activated cell sorting (FACS), and magnetically activated cell sorting (MACS), examining cell morphology using optical or confocal microscopy, and / or measuring changes in gene expression using techniques well known in the art, such as PCR and gene expression profiling. These techniques can also be used to identify cells that are positive for one or more specific markers. Fluorescence-activated cell sorting (FACS) is a well-known method for separating particles, including cells, based on the fluorescence properties of those particles (Kamarch, 1987, Methods Enzymol, 151:150-165). Laser excitation of the fluorescent portion in individual particles generates a small charge, which allows for the electromagnetic separation of positive and negative particles from a mixture. In one embodiment, cell surface marker-specific antibodies or ligands are labeled with separate fluorescent labels. Processing cells through a cell sorter allows for their separation based on their ability to bind to the antibody being used. The particles sorted by FACS can then be directly placed into individual wells of a 96-well or 384-well plate to facilitate separation and cloning.

[0173] In certain embodiments, a subset of cells is used in the manner provided herein. Methods for sorting and isolating a given cell population are well known in the Art and may be based on cell size, morphology, or intracellular or extracellular markers. Such methods include, but are not limited to, flow cytometry, flow sorting, FACS, bead-based separation (e.g., magnetic cell sorting), size-based separation (e.g., sieving, arrangement of obstacles, or filtering), sorting with microfluidics devices, antibody-based separation, sedimentation, affinity adsorption, affinity extraction, density gradient centrifugation, and laser capture microdissection.

[0174] 5.6 Method for detecting expression levels In certain embodiments, the gene expression levels of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, or SHCBP1 are determined by measuring the mRNA levels of these genes. Several methods for detecting or quantifying mRNA levels are known in the art. Exemplary methods include, but are not limited to, Northern blotting, ribonuclease-protected assays, and PCR-based methods. mRNA sequences can be used to prepare probes that are at least partially complementary. These probes can then be used to detect mRNA sequences in a sample using any suitable assay, such as PCR-based methods, Northern blotting, or dipstick assays.

[0175] In certain embodiments, nucleic acid assays can be prepared to examine immunomodulatory activity in biological samples. The assay typically comprises a solid support and at least one nucleic acid in contact with the support, the nucleic acid corresponding to at least a portion of the mRNA of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, or SHCBP1. The assay may also include means for detecting changes in mRNA expression in the sample.

[0176] In certain embodiments, the assay method may vary depending on the type of mRNA information desired. Exemplary methods include, but are not limited to, Northern blotting and PCR-based methods (e.g., RT-qPCR). Methods such as RT-qPCR can also accurately quantify the amount of mRNA in a sample.

[0177] In certain embodiments, the presence of mRNA in a sample can be determined using any suitable assay platform. For example, the assay may take the form of a dipstick, membrane, tip, disk, test strip, filter, microsphere, slide, multiwell plate, or fiber optic. The assay system may have a solid support to which nucleic acid corresponding to mRNA is attached. The solid support may include, for example, plastic, silicon, metal, resin, glass, membrane, particles, precipitate, gel, polymer, sheet, sphere, polysaccharide, capillary, film, plate, or slide. The assay components can be prepared and packaged together as an mRNA detection kit.

[0178] In certain embodiments, nucleic acids may be labeled as needed to create a population of labeled mRNA. Generally, the sample is prepared using methods well known in the art (e.g., using DNA ligase, terminal transferase, or labeling the RNA backbone, e.g., Ausubel, et al., Short Protocols in Molecular Biology, 3) rd (See Wiley & Sons ed., 1995 and Sambrook et al., Molecular Cloning: A Laboratory Manual, Third Edition, 2001, Cold Spring Harbor, NY) The sample may be labeled. In certain embodiments, the sample is labeled with a fluorescent label. Examples of fluorescent dyes include xanthene dyes, fluorescein dyes, rhodamine dyes, fluorescein isothiocyanate (FITC), 6-carboxyfluorescein (FAM), 6-carboxy-2',4',7',4,7-hexachlorofluorescein (HEX), 6-carboxy4',5'dichloro2',7'dimethoxyfluorescein (JOE or J), N,N,N',N'tetramethyl6-carboxyrhodamine (TAMRA or T), 6-carboxyx rhodamine (ROX or R), 5-carboxyrhodamine 6G (R6G5 or G5), 6-carboxyrhodamine 6G (R6G6 or G6), and rhodamine 110, cyani Examples of dyes include, but are not limited to, Cy3, Cy5 and Cy7 dyes, Alexa dyes such as Alexa-fluor-555, coumarin, diethylaminocoumarin, umbelliferone, 45-enzamide dyes such as Hoechst 33258, phenanthoridine dyes such as Texas Red, ethidium dyes, acridine dyes, carbazole dyes, phenoxazine dyes, porphyrin dyes, polymethine dyes, BODIPY dyes, quinoline dyes, pyrene, fluorescein chlorotriazinyl, R110, eosin, JOE, R6G, tetramethylrhodamine, lisamin, ROX, naptofluorescein, etc.

[0179] In certain embodiments, a typical mRNA assay method may include the steps of (1) obtaining a surface-bound target probe, (2) hybridizing a population of mRNAs to the surface-bound probe under conditions sufficient to induce specific binding, (3) a post-hybridization wash to remove nucleic acids that did not bind during hybridization, and (4) detecting the hybridized mRNA. The reagents used in each of these steps and the conditions under which they are used may vary depending on the specific application.

[0180] In certain embodiments, hybridization may be performed under suitable hybridization conditions, which may vary in stringency as needed. Typical conditions are sufficient to produce a probe / target complex on a solid surface between complementary binding members, i.e., a surface-bound target probe and complementary mRNA in the sample. In certain embodiments, stringent hybridization conditions may be used.

[0181] In certain embodiments, hybridization is typically performed under stringent hybridization conditions. Standard hybridization techniques (e.g., under conditions sufficient to result in specific binding of target mRNA in the sample to the probe) are described in Kallioniemi et al., Science 258:818-821 (1992) and International Publication No. 93 / 18186. Several general technique guides are available, e.g., Tijssen, Hybridization with Nucleic Acid Probes, Parts I and II (Elsevier, Amsterdam 1993). For a description of suitable techniques for in-situ hybridization, please refer to Gall et al. Meth. Enzymol., 21:470-480 (1981) and Angerer et al. in Genetic Engineering: Principles and Methods (Setlow and Hollaender, Eds.) Vol 7, pgs 43-65 (Plenum Press, New York 1985). The selection of appropriate conditions, including temperature, salt concentration, polynucleotide concentration, hybridization time, and stringency of washing conditions, will depend on the experimental design, including the sample source, the properties of the capture agent, and the expected degree of complementarity, and can be determined by those skilled in the art as a matter of routine experimentation.

[0182] In certain embodiments, those skilled in the art will readily recognize that alternative, but equivalent, hybridization and washing conditions may be used to provide similar stringency conditions.

[0183] In certain embodiments, after the mRNA hybridization procedure, the surface-bound polynucleotides are typically washed to remove unbound nucleic acids. Washing can be performed using any convenient washing protocol, and the washing conditions are typically stringent, as described above. Hybridization of the target mRNA to the probe is then detected using standard techniques.

[0184] In certain embodiments, other methods, such as PCR-based methods, may also be used to track the expression of the genes TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, or SHCBP1. Examples of PCR methods can be found in the literature. Examples of PCR assays can be found in U.S. Patent No. 6,927,024, which is incorporated herein by reference in its entirety. Examples of RT-PCR methods can be found in U.S. Patent No. 7,122,799, which is incorporated herein by reference in its entirety. A method of fluorescence in situ PCR is described in U.S. Patent No. 7,186,507, which is incorporated herein by reference in its entirety.

[0185] In certain embodiments, real-time reverse transcription PCR (RT-qPCR) can be used for both the detection and quantification of RNA targets (Bustin, et al., 2005, Clin. Sci., 109:365-379). Quantitative results obtained by RT-qPCR are generally more informative than qualitative data. Therefore, in certain embodiments, RT-qPCR-based assays may be useful for measuring mRNA levels during cell-based assays. RT-qPCR methods are also useful for monitoring patient therapy. Examples of RT-qPCR-based methods can be found, for example, in U.S. Patent No. 7,101,663, which is incorporated herein by reference in its entirety.

[0186] In certain embodiments, quantitative results are obtained by real-time PCR, in contrast to analysis using conventional reverse transcriptase PCR and agarose gel. An additional advantage of real-time PCR is its relatively easy and convenient use. Instruments for real-time PCR, such as the Applied Biosystems 7500, are commercially available, as are reagents such as TaqMan Sequence Detection Chemistry. For example, TaqMan® gene expression assays can be used according to the manufacturer's instructions. These kits are pre-designed gene expression assays for rapid and reliable detection and quantification of human, mouse, and rat mRNA transcripts. An exemplary PCR program is, for example, 2 minutes at 50°C, 10 minutes at 95°C, 15 seconds at 95°C for 40 cycles, followed by 1 minute at 60°C.

[0187] In certain embodiments, to determine the number of cycles (referred to as CT) at which the fluorescence signal associated with a particular amplicon accumulation crosses the threshold, for example, a comparative CT relative quantification calculation method can be used, and the data can be analyzed using 7500 Real-Time PCR System Sequence Detection software v1.3. Using this method, the output is expressed as a multiplicative change in expression level. In certain embodiments, the threshold level may be selected to be automatically determined by the software. In certain embodiments, the threshold level is set to be above the baseline, but low enough to remain within the exponential growth region of the amplification curve.

[0188] In certain embodiments, the amount of RNA transcripts can be measured using techniques known to those skilled in the art. In certain embodiments, the amounts of one, two, three, four, five or more RNA transcripts are measured using deep sequencing, e.g., ILLUMINA® RNASeq, ILLUMINA® next-generation sequencing (NGS), ION TORRENT® RNA next-generation sequencing, 454® pyrosequencing, or sequencing by oligoligation detection (SOLID®). In other embodiments, the amounts of multiple RNA transcripts are measured using microarrays and / or gene chips. In certain embodiments, the amounts of one, two, three or more RNA transcripts are determined by RT-PCR. In other embodiments, the amounts of one, two, three or more RNA transcripts are measured by RT-qPCR. Techniques for performing these assays are known to those skilled in the art. In yet another embodiment, NanoString (e.g., the nCounter® miRNA expression assay provided by NanoString® Technologies) is used for RNA transcript analysis.

[0189] In certain embodiments, the protein expression levels of FOXP1, LMO2, and MUM1 are determined by measuring the protein levels of FOXP1, LMO2, and MUM1. Several protein detection and quantification methods can be used to measure protein levels. Any suitable protein quantification method can be used. In certain embodiments, antibody-based methods are used. Exemplary methods that can be used include, but are not limited to, immunoblotting (Western blotting), enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, flow cytometry, cytometric bead array, mass spectrometry, multiplex ion beam imaging (MIBI), and imaging mass cytometry (IMC). Several types of ELISA are commonly used, including direct ELISA, indirect ELISA, and sandwich ELISA.

[0190] In certain embodiments, protein levels are determined by immunohistochemistry (IHC). IHC refers to a laboratory test that uses antibodies to examine specific antigens (markers) in a tissue sample, which is a process of detecting antigens (e.g., proteins) in cells of a tissue section by utilizing the principle that antibodies specifically bind to antigens in living tissues. Antibodies are usually linked to enzymes or fluorescent dyes. Typically, when an antibody binds to an antigen in a tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope. IHC can be used to facilitate the diagnosis of diseases such as cancer. IHC can also be used to facilitate the differentiation of different types of cancer. IHC can be used to image individual components in tissues by using appropriately labeled antibodies and specifically binding them to their target antigens in situ. IHC allows for the visualization and recording of high-resolution distribution and localization of given cellular components within cells and within their appropriate histological context. While there are multiple approaches and order variations in IHC techniques, all the steps involved can generally be divided into two groups: sample preparation and sample staining. In certain embodiments, IHC is based on immunostaining of thin sections of tissue attached to individual glass slides. For comparative analysis, multiple small sections can be arranged on a single slide; this format is called a tissue microarray. In other embodiments, IHC is performed by using high-throughput sample preparation and sample staining.

[0191] In certain embodiments, the sample can be visualized by either optical microscopy or fluorescence microscopy. In certain embodiments, antigen detection in tissue can be carried out using an antibody conjugated to an enzyme (horseradish peroxidase) and utilizing a chromogenic substrate that can be detected by optical microscopy.

[0192] In certain embodiments, the sample (e.g., tissue from a patient) is rapidly frozen in liquid nitrogen, isopentane, or dry ice. In other embodiments, the sample (e.g., tissue from a patient) is fixed in formaldehyde and embedded in paraffin wax (FFPE). In both of the above methods, the tissue or tissue section can be mounted on a slide before staining. In yet another embodiment, the IHC-free floating technique may be used, in which the entire IHC procedure is performed in liquid to increase antibody binding and penetration, and mounting to the slide is done only at the completion of the experiment. IHC-free floating appears to be most prevalent in neuroscience research. If analysis of the tissue by electron microscopy is desired, the tissue can be embedded in an acrylate resin such as glycol methacrylate (GMA), a technique known as IHC-resin.

[0193] In certain embodiments, IHC can be carried out using the methods described in the following embodiment section.

[0194] 5.7 Kit In another embodiment, what is provided herein is a kit for carrying out the methods provided herein. In a particular embodiment, what is provided herein is a kit comprising a drug for determining the expression level (e.g., mRNA level or protein level) of a specific biomarker for identifying a subject having a subtype of follicular lymphoma (FL), selectively treating the subtype of FL, identifying a subject likely to be responsive to FL treatment, and predicting the subject's responsiveness to FL treatment. In a particular embodiment, the subtype of FL is activated / memory B-cell-like (ABC / MEM-like) FL. In a particular embodiment, the subtype of FL is germinal center B-cell-like (GCB-like) FL. In a particular embodiment, the kit includes instructions for identifying a subject having a subtype of FL, selectively treating the subtype of FL, and / or identifying a subject likely to be responsive to FL treatment, and predicting the subject's responsiveness to FL treatment.

[0195] In certain embodiments, the herein provides a kit for identifying a subject having ABC / MEM-like FL, comprising a drug for determining the gene expression level of at least one biomarker in a sample from the subject. In certain embodiments, the kit further includes instructions for determining a composite score based on the gene expression level of at least one biomarker, and instructions for identifying a subject having ABC / MEM-like FL based on the composite score. In certain embodiments, the kit further includes instructions for administering treatment for ABC / MEM-like FL to a subject identified as having ABC / MEM-like FL. In certain embodiments, the kit further includes equipment for obtaining a sample from the subject.

[0196] In certain embodiments, provided herein is a kit for selectively treating subjects having FL, comprising a drug for determining the gene expression level of at least one biomarker in a sample. In certain embodiments, the kit further includes instructions for determining a composite score based on the gene expression level of at least one biomarker, instructions for identifying a subject having ABC / MEM-like FL based on the composite score, and instructions for administering ABC / MEM-like FL treatment (e.g., ABC / MEM-like FL treatment disclosed in Section 5.3) to a subject identified as having ABC / MEM-like FL. In certain embodiments, the kit further includes equipment for obtaining a sample from a subject.

[0197] In certain embodiments, provided herein is a kit for identifying subjects likely to be responsive to ABC / MEM-like FL treatment or for predicting the responsiveness of subjects to ABC / MEM-like FL treatment, the kit comprising a drug for determining the gene expression level of at least one biomarker in a sample of the subject. In certain embodiments, the kit further comprises instructions for determining a composite score based on the gene expression level of at least one biomarker, and instructions for identifying or predicting, based on the composite score, that the subject is likely to be responsive to ABC / MEM-like FL treatment. In certain embodiments, the kit further comprises instructions for administering ABC / MEM-like FL treatment to subjects likely to be responsive to ABC / MEM-like FL treatment. In certain embodiments, the kit further comprises equipment for obtaining a sample from the subject.

[0198] In certain embodiments, provided herein is a kit for identifying a subject having GCB-like FL, comprising a drug for determining the gene expression level of at least one biomarker in a sample from the subject. In certain embodiments, the kit further comprises determining a composite score based on the gene expression level of at least one biomarker; and identifying the subject having GCB-like FL based on the composite score. In certain embodiments, the kit further comprises instructions for administering treatment for GCB-like FL to a subject identified as having GCB-like FL. In certain embodiments, the kit further comprises equipment for obtaining a sample from the subject.

[0199] In certain embodiments, provided herein is a kit for selectively treating subjects having FL, comprising a drug for determining the gene expression level of at least one biomarker in a sample. In certain embodiments, the kit further comprises: determining a composite score based on the gene expression level of at least one biomarker; identifying a subject as having GCB-like FL based on the composite score; and administering a GCB-like FL treatment (e.g., the GCB-like FL treatment disclosed in Section 5.3) to the subject identified as having GCB-like FL. In certain embodiments, the kit further comprises equipment for obtaining a sample from the subject.

[0200] In certain embodiments, provided herein is a kit for identifying subjects likely to be responsive to GCB-like FL treatment or for predicting the responsiveness of subjects to GCB-like FL treatment, the kit comprising a drug for determining the gene expression level of at least one biomarker in a sample of the subject. In certain embodiments, the kit further comprises (c) determining a composite score based on the gene expression level of at least one biomarker; and (a) identifying or predicting, based on the composite score, that the subject is likely to be responsive to GCB-like FL treatment. In certain embodiments, the kit further comprises instructions for administering GCB-like FL treatment to subjects likely to be responsive to GCB-like FL treatment. In certain embodiments, the kit further comprises equipment for obtaining a sample from the subject.

[0201] In certain embodiments of the various kits provided herein, the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1.

[0202] In certain embodiments, the sample is a peripheral blood sample. In certain embodiments, the sample is a tissue sample. In certain embodiments, the sample is a tumor biopsy. In certain embodiments, the sample disclosed herein includes FL cells. A more detailed description of the sample (e.g., biological sample) is provided in Section 5.5 below.

[0203] In certain embodiments of the various kits provided herein, the kit includes instructions for determining a composite score based on the gene expression level of at least one biomarker. In certain embodiments, the kit includes agents for determining the gene expression level of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 biomarkers selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1.

[0204] In certain embodiments of the various kits provided herein, the kit includes instructions for calculating the composite score disclosed in Section 5.2.

[0205] In another embodiment, provided herein is a kit for identifying a subject having ABC / MEM-like FL, comprising agents for determining the protein expression levels of FOXP1, LMO2, CD22, and MUM1 in a sample from the subject. In certain embodiments, the kit further includes instructions for identifying a subject having ABC / MEM-like FL based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1. In certain embodiments, the kit further includes instructions for administering treatment for ABC / MEM-like FL to a subject identified as having ABC / MEM-like FL. In certain embodiments, the kit further includes equipment for obtaining a sample from the subject.

[0206] In certain embodiments, provided herein is a kit for selectively treating subjects having FL, comprising agents for determining the protein expression levels of FOXP1, LMO2, CD22, and MUM1 in a sample. In certain embodiments, the kit further includes instructions for identifying a subject having ABC / MEM-like FL based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1, and instructions for administering ABC / MEM-like FL treatment (e.g., the ABC / MEM-like FL treatment disclosed in Section 5.3) to a subject identified as having ABC / MEM-like FL. In certain embodiments, the kit further includes equipment for obtaining a sample from the subject.

[0207] In certain embodiments, provided herein is a kit for identifying subjects likely to be responsive to ABC / MEM-like FL treatment (e.g., ABC / MEM-like FL treatment as disclosed in Section 5.3) or for predicting the responsiveness of subjects to ABC / MEM-like FL treatment, the kit comprising agents for determining the protein expression levels of FOXP1, LMO2, CD22, and MUM1 in a sample of the subject. In certain embodiments, the kit further includes instructions for identifying or predicting that a subject is likely to be responsive to ABC / MEM-like FL treatment based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1. In certain embodiments, the kit further includes instructions for administering ABC / MEM-like FL treatment to subjects likely to be responsive to ABC / MEM-like FL treatment. In certain embodiments, the kit further includes equipment for obtaining a sample from the subject.

[0208] In certain embodiments, the herein provides a kit for identifying a subject having GCB-like FL, comprising agents for determining the protein expression levels of FOXP1, LMO2, CD22, and MUM1 in a sample from the subject. In certain embodiments, the kit further includes instructions for identifying a subject having GCB-like FL based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1. In certain embodiments, the kit further includes instructions for treating a subject identified as having GCB-like FL with GCB-like FL. In certain embodiments, the kit further includes equipment for obtaining a sample from the subject.

[0209] In certain embodiments, provided herein is a kit for selectively treating subjects having FL, comprising agents for determining the protein expression levels of FOXP1, LMO2, CD22, and MUM1 in a sample. In certain embodiments, the kit further includes instructions for identifying a subject having GCB-like FL based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1, and instructions for administering GCB-like FL treatment (e.g., GCB-like FL treatment as disclosed in Section 5.3) to a subject identified as having GCB-like FL. In certain embodiments, the kit further includes equipment for obtaining a sample from the subject.

[0210] In certain embodiments, the herein provides a kit for identifying subjects likely to be responsive to GCB-like FL treatment or for predicting the responsiveness of subjects to GCB-like FL treatment, the kit comprising agents for determining the protein expression levels of FOXP1, LMO2, CD22, and MUM1 in a sample of the subject. In certain embodiments, the kit further includes instructions for identifying or predicting that a subject is likely to be responsive to GCB-like FL treatment based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1. In certain embodiments, the kit further includes instructions for administering GCB-like FL treatment to subjects identified as likely to be responsive to GCB-like FL treatment. In certain embodiments, the kit further includes equipment for obtaining a sample from the subject.

[0211] In certain embodiments of the various kits provided herein, the ABC / MEM-like therapy disclosed herein comprises a therapeutically effective amount of immunomodulatory agent (IMiD®). In certain embodiments of the various kits provided herein, the ABC / MEM-like therapy disclosed herein comprises a therapeutically effective amount of cereblon E3 ligase-modulating compound. In certain embodiments, the ABC / MEM-like therapy further comprises a therapeutically effective amount of anti-CD20 antibody. In certain embodiments, the ABC / MEM-like therapy comprises a combination of a therapeutically effective amount of IMiD® and anti-CD20 antibody. In certain embodiments, the ABC / MEM-like therapy comprises a combination of a therapeutically effective amount of cereblon E3 ligase-modulating compound and anti-CD20 antibody. Further description of the ABC / MEM-like therapy disclosed herein is provided in Section 5.3.

[0212] In certain embodiments, the GCB-like therapy disclosed herein comprises a therapeutically effective amount of an immunomodulatory agent (IMiD®), an anti-CD20 antibody, a chemotherapeutic agent, or a combination thereof. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective amount of IMiD® and an anti-CD20 antibody. In certain embodiments, the GCB-like therapy disclosed herein comprises a therapeutically effective amount of a cereblon E3 modifier, an anti-CD20 antibody, a chemotherapeutic agent, or a combination thereof. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective amount of a cereblon E3 modifier and an anti-CD20 antibody. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective amount of an anti-CD20 antibody and at least one chemotherapeutic agent. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective amount of an anti-CD20 antibody and two or more (e.g., 2, 3, 4, or 5) chemotherapeutic agents. In certain embodiments, the GCB-like therapy disclosed herein further comprises a steroid hormone. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective dose of anti-CD20 antibody, at least one chemotherapeutic agent, and a steroid hormone. In certain embodiments, the GCB-like therapy comprises a combination of a therapeutically effective dose of anti-CD20 antibody, two or more chemotherapeutic agents (e.g., two, three, four, five, or more chemotherapeutic agents), and a steroid hormone. In certain embodiments, the GCB-like therapy comprises a combination of an anti-CD20 antibody, three chemotherapeutic agents, and a steroid hormone. Further descriptions of the GCB-like therapies disclosed herein are provided in Section 5.3.

[0213] In certain embodiments of the various kits provided herein, the kit further includes a drug for measuring the protein levels of biomarkers. In certain embodiments, the kit further includes instructions for measuring the protein levels of FOXP1, LMO2, CD22, and MUM1 using the drug. In certain embodiments, the kit further includes instructions for measuring the protein levels of FOXP1, LMO2, CD22, and MUM1 using immunohistochemistry (IHC) with the drug.

[0214] In certain embodiments of the various kits provided herein, the kit provides instructions for identifying a subject as having ABC / MEM-like FL, or identifying or predicting that a subject is likely to respond to treatment for ABC / MEM-like FL, when (i) the protein expression level of FOXP1 is strong or moderate and the protein expression level of LMO2 is weak or negative; (ii) the protein expression level of FOXP1 is close to (equally strong, moderate or weak) or otherwise of no informational value, and the protein expression level of CD22 is weak; or (iii) the protein expression level of FOXP1 is close to (equally strong, moderate or weak) or otherwise of no informational value, and the protein expression level of CD22 is moderate or otherwise of no informational value, and the percentage of MUM1-positive cells in the sample is greater than approximately 15%.

[0215] In certain embodiments of the various kits provided herein, the kit is such that (i) the percentage of FOXP1-positive cells in the sample is greater than about 50%, and the percentage of LMO2-positive cells in the sample is less than about 50%, and the difference between the percentage of FOXP1-positive cells and the percentage of LMO2-positive cells in the sample is about 20% or more; (ii) the difference between the percentage of FOXP1-positive cells and the percentage of LMO2-positive cells in the sample is less than about 20%, and the CD22-positive cells in the sample are present. If the percentage is less than approximately 20%, or (iii) if the difference between the percentage of FOXP1-positive cells in the sample and the percentage of LMO2-positive cells in the sample is less than approximately 20%, and the percentage of CD22-positive cells in the sample is between approximately 20% and 80%, and the percentage of MUM1-positive cells in the sample is greater than approximately 15%, then a description is provided to identify the subject as having ABC / MEM-like FL, or to identify or predict that the subject is likely to be responsive to treatment for ABC / MEM-like FL.

[0216] In certain embodiments of the various kits provided herein, the kit provides instructions for identifying a subject as having GCB-like FL, or identifying or predicting that a subject is likely to respond to treatment for GCB-like FL, when (i) the expression level of LMO2 is strong or moderate and the expression level of FOXP1 is weak or negative; (ii) the expression level of LMO2 is close to the expression level of FOXP1 (equally strong, moderate or weak) or otherwise of no informational value, and the expression level of CD22 is strong; or (iii) the expression level of LMO2 is close to the expression level of FOXP1 (equally strong, moderate or weak) or otherwise of no informational value, and the expression level of CD22 is moderate or otherwise of no informational value, and the percentage of MUM1-positive cells in the sample is less than about 10%.

[0217] In certain embodiments of the various kits provided herein, the kit is such that (i) the percentage of LMO2-positive cells in the sample is greater than about 50%, and the percentage of FOXP1-positive cells in the sample is less than about 50%, and the difference between the percentage of LMO2-positive cells in the sample and the percentage of FOXP1-positive cells in the sample is about 20% or more; (ii) the difference between the percentage of FOXP1-positive cells in the sample and the percentage of LMO2-positive cells in the sample is less than about 20%, and the sample contains CD If the percentage of 22 cells is greater than approximately 80%, or (iii) if the difference between the percentage of FOXP1-positive cells in the sample and the percentage of LMO2-positive cells in the sample is less than approximately 20%, the percentage of CD22-positive cells in the sample is between approximately 20% and approximately 80%, and the percentage of MUM1-positive cells in the sample is less than approximately 10%, then a description is provided to identify the subject as having GCB-like FL, or to identify or predict that the subject is likely to be responsive to treatment for GCB-like FL.

[0218] In certain embodiments, the kit includes reagents necessary for performing the assay described herein in one or more other containers. In certain embodiments, the kit includes a solid support and means for detecting RNA or protein expression of at least one biomarker in a biological sample. Such kits may include, for example, dipsticks, membranes, tips, discs, test strips, filters, microspheres, slides, multiwell plates, or optical fibers. The solid support of the kit may be, for example, plastic, silicon, metal, resin, glass, membrane, particles, precipitate, gel, polymer, sheet, sphere, polysaccharide, capillary, film, plate, or slide.

[0219] In certain embodiments, the kit includes in one or more containers components for performing microarrays such as RT-PCR, RT-qPCR, deep sequencing, or NanoString assays. In certain embodiments, the kit includes a solid support, a nucleic acid in contact with the support that is complementary to mRNA of at least 10, 20, 50, 100, 200, 350 bases or more, and means for detecting mRNA expression in a biological sample.

[0220] In certain embodiments, the kit includes in one or more containers components for performing an assay capable of determining the level of one or more proteins, such as flow cytometry, ELISA, or IHC.

[0221] In certain embodiments, the kit may include materials and reagents required for the measurement of RNA or protein. In certain embodiments, such a kit may include a microarray comprising oligonucleotides and / or DNA fragments and / or RNA fragments that hybridize to one or more of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1. In certain embodiments, such a kit may include PCR primers for either or both RNA products of a gene or a subset of a gene, or cDNA copies of RNA products. In certain embodiments, such a kit may include PCR primers and probes for quantitative PCR. In certain embodiments, such a kit may include a plurality of primers and a plurality of probes, some of which have different fluorophores to enable multiplexing of a plurality of products of a gene product or a plurality of genes. In certain embodiments, such a kit may further include materials and reagents for producing cDNA from RNA. In certain embodiments, such a kit may include antibodies specific to FOXP1, LMO2, CD22, and MUM1. In addition, such a kit may include materials and reagents for isolating RNA and / or proteins from a biological sample. In addition, such a kit may include materials and reagents for synthesizing cDNA from RNA isolated from a biological sample. In certain embodiments, such a kit may include a computer program product embedded in a computer-readable medium for predicting whether a patient is responsive to the compounds described herein. In certain embodiments, the kit may include a computer program product embedded in a computer-readable medium together with instructions.

[0222] In certain embodiments, an antibody-based kit may include, for example, (1) a first antibody (which may or may not be attached to a solid support) that binds to the peptide, polypeptide, or protein of interest, and optionally, (2) a second different antibody that binds to either the peptide, polypeptide, or protein or the first antibody and is conjugated with a detectable label (e.g., fluorescent label, radioisotope, or enzyme). The antibody-based kit may also include beads for performing immunoprecipitation. Each component of the antibody-based kit is generally housed in its own suitable container. Thus, these kits generally include separate containers suitable for each antibody. Furthermore, the antibody-based kit may include instructions for performing the assay and instructions for interpreting and analyzing the data obtained by performing the assay. In specific embodiments, the kit includes instructions for predicting whether an FL patient has the ABC / MEM-like subtype or GCB-like subtype of FL.

[0223] In certain embodiments of the methods and kits provided herein, a solid phase support is used for protein purification, sample labeling, or the performance of a solid-phase assay. Examples of solid phases suitable for performing the methods disclosed herein include beads, particles, colloids, single surfaces, tubes, multi-well plates, microtiter plates, slides, membranes, gels, and electrodes. When the solid phase is a particulate material (e.g., beads), in one embodiment, it is distributed into the wells of a multi-well plate to allow parallel processing of the solid phase support.

[0224] This specification includes specific embodiments for illustrative purposes, but it will be understood from the foregoing that various modifications can be made without departing from the spirit and scope of what is provided herein. All references cited above are incorporated herein by reference in their entirety.

[0225] 6. Embodiments This disclosure includes the following non-limiting embodiments. 1. A method for identifying a subject as having activated / memory B cell-like (ABC / MEM-like) follicular lymphoma (FL), comprising: (a) determining the gene expression level of at least one biomarker in a sample from the subject, wherein the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1; (b) determining a composite score based on the gene expression level of the at least one biomarker; and (c) identifying the subject as having ABC / MEM-like FL based on the composite score A method comprising the above steps. 2. The method according to embodiment 1, further comprising treating the subject identified as having ABC / MEM-like FL with a therapeutically effective amount of an immunomodulatory drug (IMiD®) and / or a cereblon E3 ligase modulating compound. 3. A method for selectively treating a subject having FL, comprising: (a) determining the gene expression level of at least one biomarker in a sample from the subject, wherein the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1; (b) determining a composite score based on the gene expression level of the at least one biomarker; (c) identifying the subject as having ABC / MEM-like FL based on the composite score; and (d) treating the subject identified as having ABC / MEM-like FL with a therapeutically effective amount of IMiD® and / or a cereblon E3 ligase modulating compound for the treatment of ABC / MEM-like FL A method that includes this. 4. A method for identifying subjects that are likely to respond to ABC / MEM-like FL treatment, or for predicting the response of subjects to ABC / MEM-like FL treatment, (a) Determining the gene expression level of at least one biomarker in the sample of interest, wherein the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1; (b) Determining a composite score based on the gene expression level of at least one biomarker; (c) Identify or predict, based on the composite score, that subjects are likely to respond to ABC / MEM-like FL treatment; and, at the discretion of (d) administering ABC / MEM-like FL treatment to subjects who are likely to respond to ABC / MEM-like FL treatment. The treatment of ABC / MEM-like FL is a method comprising a therapeutically effective amount of IMiD® and / or a cereblon E3 ligase modulating compound. 5. IMiD® and / or Cereblon E3 ligase modulating compounds include lenalidomide, pomalidomide, thalidomide, iverdamide and formula (I) [ka] The method according to any one of Embodiments 2 to 4, selected from the group consisting of compounds and their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions and pharmaceutically acceptable salts. 6. The treatment of ABC / MEM-like FL is the method according to any one of Embodiments 2 to 5, further comprising a therapeutically effective amount of anti-CD20 antibody. 7. The method according to Embodiment 6, wherein the anti-CD20 antibody is selected from the group consisting of rituximab, obinutuzumab, ocrelizumab, and combinations thereof. 8. Treatment of ABC / MEM-like FL according to any one of Embodiments 2 to 7, comprising a therapeutically effective amount of rituximab and lenalidomide or its enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions or pharmaceutically acceptable salts. 9. Treatment of ABC / MEM-like FL involves a therapeutically effective dose of rituximab and formula (I) [ka] The method according to any one of Embodiments 2 to 7, comprising the compound or its enantiomers, mixtures of enantiomers, tautomers, isotope-substituted compounds, or pharmaceutically acceptable salts. 10. Treatment of ABC / MEM-like FL by any one of Embodiments 2 to 9, which improves overall survival, progression-free survival (PFS) and / or failure-free survival (FFS) in subjects with ACB / MEM-like FL. 11. The method according to any one of Embodiments 1 to 10, wherein the composite score is determined based on the gene expression levels of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1. 12. The method according to Embodiment 11, wherein the composite score is determined based on the sum of the weighted gene expression levels of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1. 13. The composite score is calculated using the following formula: (-12.90235 × TTC28 gene expression level) + (-17.20497 × FOXP1 gene expression level) + (-14.08426 × DOPEY2 gene expression level) + (-14.14635 × IQSEC1 gene expression level) + (-15.78924 × PTPRJ gene expression level ±13.44714) × (SLA gene expression level ±13.21572) × (CXXC5 gene expression level) + (-14.31872 × PDE4B gene expression level) + (-18.17919 × TCF4 gene expression level) + (-16.21973 × MPEG1 gene expression level) + (15. The method according to Embodiment 12, determined based on (81861 × KIAA1211 gene expression level) + (15.97033 × SCPEP1 gene expression level) + (17.50829 × RASL11A gene expression level) + (17.18333 × LMO2 gene expression level) + (15.22055 × HS2ST1 gene expression level) + (15.22908 × ENPP3 gene expression level) + (15.60008 × SH3RF1 gene expression level) + (18.07827 × SCIMP gene expression level) + (15.04494 × CCDC138 gene expression level) + (15.84456 × SHCBP1 gene expression level). 14. The method according to any one of Embodiments 1 to 13, wherein if the composite score is lower than a predetermined value, the subject is identified as having ABC / MEM-like FL, or is identified or predicted to be likely to respond to treatment for ABC / MEM-like FL, and optionally the predetermined value is zero. 15. The method according to any one of Embodiments 1 to 13, wherein if the composite score is lower than the reference score, the subject is identified as having ABC / MEM-like FL, or is identified or predicted to be likely to respond to treatment for ABC / MEM-like FL, and optionally, the reference score is derived from a healthy subject or a population of healthy subjects and is calculated in the same manner as the composite score. 16. A method for identifying a subject as having germinal center B-cell-like (GCB-like) follicular lymphoma (FL), (a) Determining the gene expression level of at least one biomarker in a sample from a subject, wherein the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1; (b) Determining a composite score based on the gene expression level of at least one biomarker; and (c) Identify the subject as having GCB-like FL based on the composite score. A method that includes this. 17. The method of Embodiment 15, further comprising treating a subject identified as having GCB-like FL with GCB-like FL. 18. A method for selectively treating subjects having FL, (a) Determining the gene expression level of at least one biomarker in the sample of interest, wherein the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1; (b) Determining a composite score based on the gene expression level of at least one biomarker; (c) Identifying subjects with GCB-like FL based on a composite score; and (d) Administer a therapeutically effective dose of GCB-like FL to subjects identified as having GCB-like FL. A method that includes this. 19. A method for identifying subjects that are likely to respond to treatment of GCB-like FL, or for predicting the response of subjects to treatment of GCB-like FL, (a) Determining the gene expression level of at least one biomarker in the sample of interest, wherein the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1; (b) Determining a composite score based on the gene expression level of at least one biomarker; and (c) Identifying or predicting, based on a composite score, that subjects are likely to respond to treatment for GCB-like FL; and, at the discretion of (d) administering GCB-like FL treatment to subjects who are likely to respond to treatment for GCB-like FL. A method that includes this. 20. Treatment of GCB-like FL according to any one of Embodiments 15 to 19, comprising a therapeutically effective dose of IMiD®, a cereblon E3 ligase modulating compound, an anti-CD20 antibody, a chemotherapeutic agent, or a combination thereof. 21. IMiD (registered trademark) and / or Cereblon E3 ligase modulating compounds include lenalidomide, pomalidomide, thalidomide, iverdamide and formula (I) [ka] The method according to Embodiment 20, selected from the group consisting of compounds and their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions and pharmaceutically acceptable salts. 22. The method according to Embodiment 20, wherein the anti-CD20 antibody is selected from the group consisting of rituximab, obinutuzumab, ocrelizumab, and combinations thereof. 23. The method according to Embodiment 20, wherein the chemotherapeutic agent is selected from the group consisting of cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and combinations thereof. 24. Treatment of GCB-like FL according to any one of Embodiments 15-20, comprising a therapeutically effective dose of anti-CD20 antibody and chemotherapeutic agent. 25. Treatment of GCB-like FL is the method according to embodiment 24, comprising rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate and prednisone in a therapeutically effective amount. 26. Treatment of GCB-like FL is the method according to any one of embodiments 15 - 20, comprising an IMiD® and / or a cereblon E3 ligase modulating compound and an anti-CD20 antibody in a therapeutically effective amount. 27. Treatment of GCB-like FL is the method according to embodiment 26, comprising rituximab and lenalidomide or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope-substituted form or a pharmaceutically acceptable salt in a therapeutically effective amount. 28. Treatment of GCB-like FL is a compound of formula (I)

Chemical formula

[0226] The following embodiments are performed using standard techniques that are well known and routine to those skilled in the art, unless otherwise described in detail. These embodiments are intended to be illustrative only.

[0227] 7.1 Example 1: Identification of activated / memory B cell signatures related to poor outcomes and sensitivity to lenalidomide in follicular lymphoma. Materials and methods Patients and specimens The RELEVANCE trial (ClinicalTrials.gov identifier: NCT01650701) demonstrated that the lenalidomide plus rituximab combination (R2) provided similar efficacy to rituximab plus chemotherapy (R-chemotherapy) after 6 years of follow-up in patients with previously untreated advanced follicular lymphoma (FL) (Morschhauser et al., N Engl J Med 2018 Sep 6;379(10):934-947, Morschhauser et al., J Clin Oncol 2022 Oct 1;40(28):3239-3245). A total of 1030 patients were randomly assigned to receive one of two regimens followed by maintenance monotherapy with rituximab. The patient's characteristics are described in detail elsewhere (Morschhauser et al., N Engl J Med 2018 Sep 6;379(10):934-947).

[0228] Pathological review and FISH analysis Prior to any treatment, formalin-fixed, paraffin-embedded (FFPE) biopsy specimens were obtained at the time of diagnosis. Patients were included in the study based on a histologically proven diagnosis of FL grade 1, 2, or 3A. FL grade 3B was excluded. To confirm the diagnosis using appropriate staining and phenotypic testing, pathological specimens were centrally reviewed by a team of specialist hematopathologists at the GELA Pathology Center (Paris, France). Pathological screening included FISH analysis using break-apart DNA probes for BCL2 / 18q21 and BCL6 / 3q27 (probes Z-2192 and Z-2177, Zytovision, Germany) and a break-apart DNA probe for MYC / 8q24 (1N6320, Abbott Laboratories, Chicago, IL). Dual-color probe 1p36 / 1q25 (Z-2075, Zytovision, Germany) was also included.

[0229] RNA sequencing analysis Due to sample availability and technical constraints, FFPE samples from 324 patients with confirmed FL tissue structure were available for DNA and mRNA extraction using a Maxwell® device, as instructed by the supplier. Scraps from each FFPE block were obtained from regions of interest containing malignant follicles representative of the entire biopsy sample. This informative set of 324 patients showed slightly better survival in both PFS and OS compared to the entire Relevance cohort.

[0230] RNA sequencing pretreatment Based on the transcript definition in Gencode version 24, RNA counts were quantified at the gene level using salmon. The counts were normalized to library size using DESeq2 sizeFactor normalization, a pseudo-count value of 1 was added, and then log2 transformed. Low-expression genes, defined as those expressed at a minimum of 0.2 counts per million in fewer than approximately 10 samples, were excluded.

[0231] Consensus clustering based on independent component analysis We developed an approach similar to non-negative matrix factorization (NMF) consensus clustering, but relying on independent component analysis (ICA) instead of NMF for signal deconvolution. ICA was performed in parallel mode using the R package fastICA, and 50 components were extracted from the normalized matrix after gene-wise standardization (to mean 0 and variance 1). Each ICA component can be viewed as a metagene, with each individual gene weighted by a coefficient that can be either positive or negative. Using the 50 ICA components, 100 gene clusters were defined. Each component defined one cluster consisting of all genes with a strong negative weight (threshold ≤ -3) and another cluster consisting of all genes with a strong positive weight (threshold ≥ 3). This process was repeated 100 times, and the consensus matrix was calculated to record the percentage of ICA runs in which each pair of genes belonged to a common cluster. This consensus matrix was used as the similarity matrix to perform hierarchical clustering by ward.D2 aggregation, followed by cluster assignment using DynamicTreeCut (Langfelder et al. 2008). The resulting clusters were then scored for individual patients by calculating the average of the standardized expression levels of all genes within the cluster. Following this step, the resulting clusters were filtered based on the following criteria: 1) excluding clusters with low consistency that grouped genes that were part of the same initial cluster for less than 50% (on average) of ICA runs; 2) utilizing clusters containing fewer than 20 genes; and 3) clusters where score variability was primarily driven by a small number of outlier samples where the standard deviation of the cluster score exceeded 1.5 times the median absolute deviation.

[0232] Score design for linear predictors A Linear Predictor Score Classifier (LPS) was designed to classify samples into either the FL ABC / MEM-like subtype or the FL GCB-like subtype based on the gene with the highest discriminative power. A difference analysis was performed on the initial classification of samples, defined by unsupervised hierarchical clustering (Euclidean distance, ward.D2), based on the combined standardized expression levels of all genes from both signatures. To distinguish between the two clusters, an adjusted t-statistic (Limma-like) was calculated for each gene from both signatures, and the top 10 protein-coding genes were selected in both directions (20 genes). The linear predictor score was then calculated by multiplying the individual standardized gene expression levels by the t-statistics associated with these 20 genes as weights. This process was performed using the LPS package (v1.0.16) in an R computing environment. This package calculates the LPS20 score as a weighted sum of the expression levels of the 20 genes and classifies cases based on the score threshold.

[0233] statistical analysis Statistical analysis was performed using R. Survival analysis was performed using the coxph function for survival analysis, and survival curves were plotted using the Survminer R package. Two patients were excluded from the analysis because they did not receive treatment. Fisher's exact test was used for frequency comparisons and for overpopulation of gene sets.

[0234] Analysis of gene set overpopulation Gene sets were obtained from MSigDB (Hallmark, c2, c6, and c8 collections) and the LLMPP signature database. Genes were matched between ICA consensus cluster signatures and gene set collections using NCBI entrez gene IDs. Overpopulation was assessed using one-sided Fisher's exact test, and p-values ​​were adjusted using Benjamini-Hochberg correction, taking into account the number of gene sets tested.

[0235] immunohistochemistry To establish an immunoscore (FLCM score) based on immunohistochemistry (IHC) detection of FOXP1 / LMO2 / CD22 / MUM1, IHC was used on either whole sections of FFPE biopsy specimens or tissue microarrays (TMAs), and the correlation between RNA-seq and IHC profiles was analyzed. The same specimen was used for either RNA-seq or IHC analysis. For TMA construction, during the pathological review of each case, regions containing malignant follicles representative of the entire biopsy specimen and lacking fibrotic areas were marked on paraffin blocks. Then, cylindrical objects with a diameter of 1 mm were collected from three different regions and included in the TMA blocks. FOXP1 (clone D35D10, Cell Signaling Technologies, Ozyme) was used at a dilution of 1 / 200 (Envision Flex diluent, Agilent Technologies) after 20 minutes of heat-induced epitope recovery in ER2 buffer (pH 9, Leica Biosystems). LMO2 (pre-prepared, clone RBT-LMO2, BioSB, Diagnostics) was used after 30 minutes of heat-induced epitope recovery in ER1 buffer (pH 6, Leica Biosystems). Immunostaining of both FOXP1 and LMO2 was performed on a Leica BOND RX automated slide staining system (Leica Biosystems) using the LEICA Bond polymer DAB refine detection kit. Slides were counterstained with hematoxylin, dehydrated, and mounted using xylene-based mounting (Sakura TissueTek, Sakura FineTek). MUM1 (pre-prepared, clone EP190, Roche Diagnostics) was used after 32 minutes of heat-induced epitope recovery in CC1 buffer (pH 6, Roche Diagnostics) using the Benchmark Optiview DAB detection kit on a Benchmark ULTRA automated slide staining system (Roche Diagnostics). The slides were counterstained with hematoxylin, dehydrated, and mounted using xylene-based mounting (Sakura TissueTek, Sakura FineTek).

[0236] result Gene expression profiles highlight the subcategorization of FL tumors based on cellular origin within germinal center (GC)-like subgroups and activated / memory B cell (ABC / MEM)-like subgroups. To investigate the biological basis of transcriptome heterogeneity in FL tumors, we performed exploratory unsupervised analyses of gene expression data. Using a consensus clustering approach based on independent component analysis (ICA), we extracted 46 gene clusters and performed functional enrichment on the gene clusters whose association with clinical outcomes was tested.

[0237] Of the 46 identified gene expression signatures (GES), two GES showed an inverse and treatment-dependent association with progression-free survival (PFS). The first GES, called CC17 (213 genes), which is strongly inversely correlated with the first GES, enriches genes expressed in DLBCL of the GCB subtype (25% of genes belong to the LLMPP:GCBDLBCL-3 signature, FDR=9.35e-38, Supplementary Table 2). On the other hand, the second GES, called CC21 (179 genes), enriches genes expressed in DLBCL of the ABC subtype (17% of genes belong to the LLMPP:ABCDLBCL-4 signature, FDR=2.5e-16). Furthermore, as shown by comparisons with several published datasets, genes expressed in normal memory B cells were also enriched (Stewart et al., Front Immunol. 2021 Mar 18;12:602539, Attaf et al., Eur J Immunol. 2021 Nov;51(11):2555-2567, Wang et al., Nat Commun. 2022 Nov 9;13(1):6772).

[0238] The CC17 and CC21 gene expression signatures were integrated into a 20-gene-based linear predictor score (LPS20) that classified patients into either the ABC / MEM-like FL subtype (n=160) or the GCB-like FL subtype (n=164) (Figure 1).

[0239] The ABC / MEM signature predicts poor outcomes and susceptibility to lenalidomide in FL patients. In the R-chemotherapy arm, the 6-year PFS (45% [35-59]) in ABC / MEM-like patients was significantly shorter than that of GCB-like patients (67% [59-80]) (HR=2.13 [1.30-3.51], p=0.003) (Figure 2A). In the R2 arm, PFS was similar for both the GCB-like and ABC / MEM-like subgroups (65% vs. 62%, HR=1.04 [0.61-1.77], p=0.9) (Figure 2B). In the multivariate model including FLIPI, the association between subtype and outcome remained significant for R-chemotherapy patients (adjusted HR=2.15 [1.31-3.53], p=0.002), and similarly significant for treatment dependency (subtype × treatment interaction, p=0.041). In ABC / MEM-like patients with FLIPI ≥ 2, a significant R2 benefit was observed compared to R-chemotherapy (HR = 0.46 [0.28~0.75], p = 0.002). In contrast, no R2 benefit was observed in GC-like patients with FLIPI ≥ 2 (p = 0.88). Among patients with FLIPI > 2 treated with R-chemotherapy, outcomes in GC-like patients were far better than in ABC / MEM-like patients (p = 0.00034).

[0240] The poor prognostic value of the ABC / MEM signature can be validated in previously reported FL cohorts treated with R-chemotherapy. The prognostic value of COO was examined in two independent FL cohorts treated with R-chemotherapy from LYSA (PRIMA, n=134) and BCCA (GSE119214, n=137). In PRIMA, the ABC / MEM-like subtype was associated with shorter PFS (compared to GCB-like), but this was limited to patients with FLIPI ≥ 2 (n=111, HR=1.72 [1.01~2.93], p=0.044) (Figure 3A). In the BCCA cohort, since only 17 / 20 genes had been assayed in publicly available datasets, classifier fitting was necessary, and the ABC / MEM-like subtype was associated with inferior FFS (HR=1.78 [1.1~2.87], p=0.019) and overall survival (HR=2.13 [1.18~3.82], p=0.012) (Figure 3B).

[0241] Comparison of ABC / MEM signatures with previously reported prognostic GES The value of the previously developed 23-gene score (GS23) in patients receiving R-chemotherapy in the PRIMA trial (Huet et al., Lancet Oncol. 2018 Apr;19(4):549-561) was analyzed in the Relevance cohort. GS23 shared two genes with the CC17 signature and six genes with the CC21 signature. As expected, GS23 was associated with PFS in the Relevance arm of R-chemotherapy (p=0.013). In contrast, GS23 in the overall cohort of Relevance patients only showed a trend toward significance (p=0.058) and was not significant in the R2 arm (p=0.97).

[0242] The value of 33 recently described gene signatures (GS33) was evaluated in Relevance patients. The GS33 gene signatures shared 9 / 33 and 3 / 33 common genes with the CC17 gene signatures (SYT17, PRPSAP2, SSBP2, HS2ST1, ENPP3, ZFAND4, MARCKSL1, ASB13, S1PR2) and the CC21 gene signatures (NLRC5, SAMD9L, KIF13B), respectively. Since individual gene weights were not provided, a simple scoring based on the mean of standardized gene expression levels was used, with ABC genes weighted +1 and GCB genes weighted -1. This method showed that GS33 did not correlate with PFS in the Relevance cohort (p=0.6), and also did not correlate with PFS in the R-chemotherapy arm and the R2 arm (p=0.11 and p=0.39, respectively).

[0243] Cases of GCB-like FL show a mutation profile reminiscent of GC-DLBCL, while cases of ABC / MEM-like FL show an enrichment of mutations in the KMT2D gene and ATPase gene. WES analysis was informative in cases including Y GCB type and Z ABC type FL cases. GC subtype cFL cases exhibited a WES profile reminiscent of GC-DLBCL and had high-frequency mutations targeting TNFSFR14, EZH2, STAT6, SOCS1, HVCN1, KLHL6, and GNAI2 (Figure 4). In particular, compared to the ABC / MEM subtype, GC-like FL showed an overabundance of mutations in TNFSFR14, EZH2, SOCS1, and STAT6. In contrast, ABC / MEM FL cases showed a greater number of mutations in KMT2D, ATP6V1B2, and ATP6AP1 (Figure 4).

[0244] The ABC / MEM-like FL subtype exhibits a higher frequency of BCL6 translocations. FISH analysis was informative in 342 cases (including 16 cases with only one or two informative FISH probes). Of these 342 cases, the number of informative RNA-seq cases was 255 for BCL2, 256 for BCL6, and 253 for MYC, respectively. BCL2 and BCL6 rearrangements were observed in 312 / 342 cases (91%) and 50 / 342 cases (14.5%), respectively. 1p36 deletions were present in 49 cases (14.5%), while MYC rearrangements were detected in 6 cases (1.75%), including 5 cases with MYC / BCL2 double hits. There was no correlation between GC subtype and ABC / MEM subtype with the presence of BCL2 cleavage (p=0.27), the presence of Myc cleavage (p=0.18), or the presence of 1p36 deletion. In contrast, BCL6 cleavage was more frequent in the ABC subtype (20% vs. 9%, p=0.037).

[0245] Routine immunohistochemistry-based algorithms enable subtyping of FFPE FL biopsies. To enable easy subtyping of FL tumors in routine procedures, we developed an immunoscore (called the FLCM score) based on IHC detection of FOXP1, LMO2, CD22, and MUM1. The three targets were selected because they significantly influence either an ABC-like signature (FOXP1 and MUM1) or a GCB-like signature (LMO2). Indeed, the corresponding genes are among the top genes influencing either signature, including FOXP1 and LMO2 in particular (see Table 1). Another reason for their selection was the reliability of each immunodetection and the simplicity and clarity of their interpretation.

[0246] [Table 1]

[0247] The simplest interpretation used an algorithm in which FOXP1 and LMO2 were tested first (Figure 5). If there was a clear difference in the staining patterns of the two antibodies with respect to the intensity and percentage of positive cells, the sample was classified as ABC / MEM-like FL if there was strong staining for FOXP1 and weak staining for LMO2 (Figure 6A). In contrast, if the sample contained weak staining for FOXP1 and strong staining for LMO2, the sample was classified as GCB-like FL (Figure 6B). Samples could also be stained for CD22 and MUM1 to classify them as either ABC / MEM-like FL or GCB-like FL. For example, if the sample contained weak staining for FOXP1, strong staining for LMO2, strong staining for CD22, and weak staining for MUM1, the sample was classified as GCB-like FL (Figure 7A). MUM1 could also be used if there was no clear difference between FOXP1 and LMO2, and there was weak staining for CD22. For example, if a sample showed moderate staining for both FOXP1 and LMO2, weak staining for CD22, and positive staining for MUM1 in more than approximately 15% of cells, the sample was classified as ABC / MEM-like FL (Figure 7B). Similarly, if a sample showed strong staining for FOXP1 and LMO2, moderate staining for CD22, and positive staining for MUM1 in less than approximately 10% of cells, the sample was classified as GCB-like FL (Figure 8).

[0248] These results confirm that FL tumors can be subdivided into cell-origin-based ABC / MEM-like or GCB-like subtypes, and that this classification has reliable prognostic importance, as demonstrated by its validation in two other cohorts of IC-treated patients using a reduced 20-gene panel predictor. Notably, a simple and reliable IHC algorithm was developed using four antibodies (FLCM score), which holds sufficient information to assess this subtype using routine FFPE samples in future cohorts and is therefore a promising therapeutic diagnostic tool. The FLCM score identified ABC / MEM-like FL patients as a high-risk subgroup with a poorer outcome when treated with R-chemotherapy. However, ABC / MEM-like FL patients have a better prognosis when treated with the immunomodulatory regimen R2 compared to ABC / MEM-like FL patients treated with R-chemotherapy.

Claims

1. A method for identifying a subject as having activated / memory B-cell-like (ABC / MEM-like) follicular lymphoma (FL), (a) Determining the gene expression level of at least one biomarker in a sample from the subject, wherein the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1; (b) Determining a composite score based on the gene expression level of at least one biomarker; and (c) Identifying that the subject has ABC / MEM-like FL based on the composite score. A method that includes this.

2. The method according to claim 1, further comprising treating the subject identified as having ABC / MEM-like FL with a therapeutically effective amount of an immunomodulator (IMiD®) and / or a cereblon E3 ligase modulating compound for ABC / MEM-like FL.

3. A method for selectively treating subjects with FL, (a) Determining the gene expression level of at least one biomarker in the sample of interest, wherein the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1; (b) Determining a composite score based on the gene expression level of at least one biomarker; (c) Identifying that the subject has ABC / MEM-like FL based on the composite score; and (d) The subject identified as having ABC / MEM-like FL is treated with ABC / MEM-like FL containing a therapeutically effective amount of IMiD® and / or a cereblon E3 ligase modulating compound. A method that includes this.

4. A method for identifying subjects who are likely to respond to treatment for ABC / MEM-like FL, or for predicting the response of subjects to treatment for ABC / MEM-like FL, (a) Determining the gene expression level of at least one biomarker in the sample of interest, wherein the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1; (b) Determining a composite score based on the gene expression level of at least one biomarker; (c) Identifying or predicting, based on the composite score, that the subject is likely to be responsive to the ABC / MEM-like FL treatment; and, optionally, (d) administering the ABC / MEM-like FL treatment to the subject that is likely to be responsive to the ABC / MEM-like FL treatment. The treatment of ABC / MEM-like FL comprises a therapeutically effective amount of IMiD® and / or a cereblon E3 ligase modulating compound.

5. The aforementioned IMiD® and / or Cereblon E3 ligase modulating compounds include lenalidomide, pomalidomide, thalidomide, iverdamide and formula (I) 【Chemistry 1】 The method according to any one of claims 2 to 4, selected from the group consisting of compounds and their enantiomers, mixtures of enantiomers, tautomers, isotope-substituted compounds and pharmaceutically acceptable salts.

6. The method according to any one of claims 2 to 5, wherein the treatment for ABC / MEM-like FL further comprises a therapeutically effective amount of anti-CD20 antibody.

7. The method according to claim 6, wherein the anti-CD20 antibody is selected from the group consisting of rituximab, obinutuzumab, ocrelizumab, and combinations thereof.

8. The treatment for ABC / MEM-like FL according to any one of claims 2 to 7, comprising a therapeutically effective amount of rituximab and lenalidomide or its enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions or pharmaceutically acceptable salts.

9. The aforementioned treatment for ABC / MEM-like FL involves a therapeutically effective dose of rituximab and formula (I) 【Chemistry 2】 The method according to any one of claims 2 to 7, comprising the compound or its enantiomers, mixtures of enantiomers, tautomers, isotope-substituted compounds or pharmaceutically acceptable salts.

10. The method according to any one of claims 2 to 9, wherein the treatment for ABC / MEM-like FL improves the overall survival, progression-free survival (PFS), and / or failure-free survival (FFS) of the subject having ACB / MEM-like FL.

11. The method according to any one of claims 1 to 10, wherein the composite score is determined based on the gene expression levels of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1.

12. The method according to claim 11, wherein the composite score is determined based on the sum of the weighted gene expression levels of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1.

13. The composite score is calculated using the following formula: (-12.90235 × TTC28 gene expression level) + (-17.20497 × FOXP1 gene expression level) + (-14.08426 × DOPEY2 gene expression level) + (-14.14635 × IQSEC1 gene expression level) + (-15.78924 × PTPRJ gene expression level) + (-13.44714 × SLA gene expression level) + (-13.21572 × CXXC5 gene expression level) + (-14.31872 × PDE4B gene expression level) + (-18.17919 × TCF4 gene expression level) + (-16.21973 × MPEG1 gene expression level) + (15. The method according to claim 12, determined based on (81861 × KIAA1211 gene expression level) + (15.97033 × SCPEP1 gene expression level) + (17.50829 × RASL11A gene expression level) + (17.18333 × LMO2 gene expression level) + (15.22055 × HS2ST1 gene expression level) + (15.22908 × ENPP3 gene expression level) + (15.60008 × SH3RF1 gene expression level) + (18.07827 × SCIMP gene expression level) + (15.04494 × CCDC138 gene expression level) + (15.84456 × SHCBP1 gene expression level).

14. The method according to any one of claims 1 to 13, wherein if the composite score is lower than a predetermined value, the subject is identified as having ABC / MEM-like FL, or is identified or predicted to be highly likely to respond to the treatment for ABC / MEM-like FL, and optionally the predetermined value is zero.

15. The method according to any one of claims 1 to 13, wherein if the composite score is lower than the reference score, the subject is identified as having ABC / MEM-like FL, or is identified or predicted to be likely to be responsive to the treatment for ABC / MEM-like FL, and optionally the reference score is derived from a healthy subject or a group of healthy subjects and is calculated in the same manner as the composite score.

16. A method for identifying a subject as having germinal center B-cell-like (GCB-like) follicular lymphoma (FL), (a) Determining the gene expression level of at least one biomarker in a sample from the subject, wherein the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1; (b) Determining a composite score based on the gene expression level of at least one biomarker; and (c) Based on the composite score, identify the subject as having the GCB-like FL. A method that includes this.

17. The method according to claim 15, further comprising treating the subject identified as having GCB-like FL for GCB-like FL.

18. A method for selectively treating subjects with FL, (a) Determining the gene expression level of at least one biomarker in the sample of interest, wherein the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1; (b) Determining a composite score based on the gene expression level of at least one biomarker; (c) Identifying that the subject has GCB-like FL based on the composite score; and (d) Providing a therapeutically effective dose of GCB-like FL to the subject identified as having GCB-like FL. A method that includes this.

19. A method for identifying subjects who are likely to respond to treatment for GCB-like FL, or for predicting the response of subjects to treatment for GCB-like FL, (a) Determining the gene expression level of at least one biomarker in the sample of interest, wherein the biomarker is selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1; (b) Determining a composite score based on the gene expression level of at least one biomarker; (c) Identifying or predicting, based on the composite score, that the subject is likely to be responsive to the GCB-like FL treatment; and, optionally, (d) administering the GCB-like FL treatment to the subject that is likely to be responsive to the GCB-like FL treatment. A method that includes this.

20. The treatment for GCB-like FL according to any one of claims 15 to 19, comprising a therapeutically effective amount of IMiD®, a cereblon E3 ligase modulating compound, an anti-CD20 antibody, a chemotherapeutic agent, or a combination thereof.

21. The aforementioned IMiD® and / or Cereblon E3 ligase modulating compounds include lenalidomide, pomalidomide, thalidomide, iverdamide and formula (I) 【Transformation 3】 The method according to claim 20, selected from the group consisting of compounds and their enantiomers, mixtures of enantiomers, tautomers, isotope-substituted compounds and pharmaceutically acceptable salts.

22. The method according to claim 20, wherein the anti-CD20 antibody is selected from the group consisting of rituximab, obinutuzumab, ocrelizumab, and combinations thereof.

23. The method according to claim 20, wherein the chemotherapeutic agent is selected from the group consisting of cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and combinations thereof.

24. The method according to any one of claims 15 to 20, wherein the treatment for GCB-like FL comprises the therapeutically effective amount of the anti-CD20 antibody and the chemotherapeutic agent.

25. The method according to claim 24, wherein the treatment for GCB-like FL comprises the therapeutically effective amounts of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone.

26. The treatment for GCB-like FL according to any one of claims 15 to 20, comprising the therapeutically effective amount of the IMiD® and / or cereblon E3 ligase modulating compound and the anti-CD20 antibody.

27. The method according to claim 26, wherein the treatment for GCB-like FL comprises a therapeutically effective amount of rituximab and lenalidomide or its enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions or pharmaceutically acceptable salts.

28. The aforementioned treatment for GCB-like FL involves the therapeutically effective dose of rituximab and formula (I) 【Chemistry 4】 The method according to claim 26, comprising the compound or its enantiomers, mixtures of enantiomers, tautomers, isotope-substituted compounds or pharmaceutically acceptable salts.

29. The method according to any one of claims 15 to 28, wherein the composite score is determined based on the gene expression levels of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1.

30. The method according to claim 29, wherein the composite score is determined based on the sum of the weighted gene expression levels of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138, and SHCBP1.

31. The composite score is calculated using the following formula: (-12.90235 × TTC28 gene expression level) + (-17.20497 × FOXP1 gene expression level) + (-14.08426 × DOPEY2 gene expression level) + (-14.14635 × IQSEC1 gene expression level) + (-15.78924 × PTPRJ gene expression level) + (-13.44714 × SLA gene expression level) + (-13.21572 × CXXC5 gene expression level) + (-14.31872 × PDE4B gene expression level) + (-18.17919 × TCF4 gene expression level) + (-16.21973 × MPEG1 gene expression level) + (15. The method according to claim 30, determined based on (81861 × KIAA1211 gene expression level) + (15.97033 × SCPEP1 gene expression level) + (17.50829 × RASL11A gene expression level) + (17.18333 × LMO2 gene expression level) + (15.22055 × HS2ST1 gene expression level) + (15.22908 × ENPP3 gene expression level) + (15.60008 × SH3RF1 gene expression level) + (18.07827 × SCIMP gene expression level) + (15.04494 × CCDC138 gene expression level) + (15.84456 × SHCBP1 gene expression level).

32. The method according to any one of claims 15 to 31, wherein if the composite score is higher than a predetermined value, the subject is identified as having GCB-like FL, or is identified or predicted to be highly likely to be responsive to the treatment for GCB-like FL, and optionally the predetermined value is zero.

33. The method according to any one of claims 15 to 31, wherein if the composite score is higher than the reference score, the subject is identified as having GCB-like FL, or is identified or predicted to be highly likely to respond to the treatment for GCB-like FL, and optionally the reference score is derived from a healthy subject or a group of healthy subjects and is calculated in the same manner as the composite score.

34. The method according to any one of claims 1 to 33, wherein the gene expression level of the at least one biomarker is at the mRNA level.

35. The method according to claim 34, wherein the gene expression level is measured by RNA sequencing or a PCR-based quantification method.

36. A method for identifying a subject as having ABC / MEM-like FL, (a) Determining the protein expression levels of FOXP1, LMO2, CD22, and MUM1; and (b) Identifying that the subject has the ABC / MEM-like FL based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1. A method that includes this.

37. The method according to claim 36, further comprising administering a therapeutically effective amount of an immunomodulator (IMiD®) and / or a cereblon E3 ligase modulating compound to the subject identified as having ABC / MEM-like FL.

38. A method for selectively treating subjects with FL, (a) Determine the protein expression levels of FOXP1, LMO2, CD22, and MUM1; (b) Identifying that the subject has ABC / MEM-like FL based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1; and (c) Administering a therapeutically effective dose of IMiD® and / or a cereblon E3 ligase modulating compound to the subject identified as having ABC / MEM-like FL. A method that includes this.

39. A method for identifying subjects who are likely to respond to treatment for ABC / MEM-like FL, or for predicting the response of subjects to treatment for ABC / MEM-like FL, (a) Determine the protein expression levels of FOXP1, LMO2, CD22, and MUM1; (b) Identifying or predicting, based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1, that the subject is likely to be responsive to the ABC / MEM-like FL treatment; and, optionally, (c) administering the ABC / MEM-like FL treatment to the subject that is likely to be responsive to the ABC / MEM-like FL treatment. The treatment of ABC / MEM-like FL is a method comprising IMiD® and / or a cereblon E3 ligase modulating compound.

40. The aforementioned IMiD® and / or Cereblon E3 ligase modulating compounds include lenalidomide, pomalidomide, thalidomide, iverdamide and formula (I) 【Transformation 5】 The method according to any one of claims 37 to 39, selected from the group consisting of compounds and their enantiomers, mixtures of enantiomers, tautomers, isotope-substituted compounds and pharmaceutically acceptable salts.

41. The method according to any one of claims 37 to 40, wherein the treatment for ABC / MEM-like FL further comprises a therapeutically effective amount of anti-CD20 antibody.

42. The method according to claim 41, wherein the anti-CD20 antibody is selected from the group consisting of rituximab, obinutuzumab, ocrelizumab, and combinations thereof.

43. The treatment for ABC / MEM-like FL according to any one of claims 37 to 42, comprising a therapeutically effective amount of rituximab and lenalidomide or its enantiomers, mixtures of enantiomers, tautomers, isotope substitutions or pharmaceutically acceptable salts.

44. The aforementioned treatment for ABC / MEM-like FL involves a therapeutically effective dose of rituximab and formula (I) 【Transformation 6】 The method according to any one of claims 37 to 42, comprising a compound or its enantiomer, mixture of enantiomers, tautomer, isotope-substituted or pharmaceutically acceptable salt.

45. The treatment for ABC / MEM-like FL is the method according to any one of claims 37 to 44, wherein the treatment improves the overall survival, PFS and / or FFS of the subject having ACB / MEM-like FL.

46. The method according to any one of claims 37 to 45, wherein the protein expression levels of FOXP1, LMO2, CD22, and MUM1 are protein levels.

47. The method according to claim 46, wherein the protein level is measured using immunohistochemistry (IHC), multiplex ion beam imaging (MIBI), or imaging mass cytometry (IMC).

48. (i) If the protein expression level of FOXP1 is strong or moderate and the protein expression level of LMO2 is weak or negative, (ii) If the protein expression level of FOXP1 is close to (equivalently strong, moderate, or weak) the protein expression level of LMO2, or if otherwise it has no informational value, and the protein expression level of CD22 is weak, (iii) If the protein expression level of FOXP1 is close to (equivalently strong, moderate, or weak) the protein expression level of LMO2, or otherwise has no informational value, and the protein expression level of CD22 is moderate or otherwise has no informational value, and the percentage of MUM1-positive cells in the sample is greater than approximately 15%, The method according to claim 47, wherein the subject is identified as having ABC / MEM-like FL, or is identified or predicted to be highly likely to be responsive to the treatment of ABC / MEM-like FL.

49. (i) If the percentage of FOXP1-positive cells in the sample is greater than approximately 50%, and the percentage of LMO2-positive cells in the sample is less than approximately 50%, and the difference between the percentage of FOXP1-positive cells in the sample and the percentage of LMO2-positive cells in the sample is approximately 20% or more, (ii) If the difference between the percentage of FOXP1-positive cells in the sample and the percentage of LMO2-positive cells in the sample is less than approximately 20%, and the percentage of CD22-positive cells in the sample is less than approximately 20%, or (iii) If the difference between the percentage of FOXP1-positive cells in the sample and the percentage of LMO2-positive cells in the sample is less than approximately 20%, and the percentage of CD22-positive cells in the sample is between approximately 20% and approximately 80%, and the percentage of MUM1-positive cells in the sample is greater than approximately 15%, The method according to claim 47 or 48, wherein the subject is identified as having ABC / MEM-like FL, or is identified or predicted to be highly likely to be responsive to the treatment for ABC / MEM-like FL.

50. A method for identifying a subject that has GCB-like FL, (a) Determining the protein expression levels of FOXP1, LMO2, CD22, and MUM1; and (b) Identifying that the subject has the GCB-like FL based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1. A method that includes this.

51. The method according to claim 50, further comprising treating the subject identified as having GCB-like FL for GCB-like FL.

52. A method for selectively treating subjects with FL, (a) Determine the protein expression levels of FOXP1, LMO2, CD22, and MUM1; (b) Identifying the subject to have a GCB-like FL based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1; and (c) Providing a therapeutically effective dose of GCB-like FL to the subject identified as having GCB-like FL. A method that includes this.

53. A method for identifying subjects who are likely to respond to treatment for GCB-like FL, or for predicting the response of subjects to treatment for GCB-like FL, (a) Determine the protein expression levels of FOXP1, LMO2, CD22, and MUM1; (b) Identifying or predicting, based on the protein expression levels of FOXP1, LMO2, CD22, and MUM1, that the subject is likely to be responsive to the GCB-like FL treatment; and, optionally, (c) administering the GCB-like FL treatment to the subject that is likely to be responsive to the GCB-like FL treatment. A method that includes this.

54. The treatment for GCB-like FL according to any one of claims 51 to 53, comprising a therapeutically effective amount of IMiD®, a cereblon E3 ligase modulating compound, an anti-CD20 antibody, a chemotherapeutic agent, or a combination thereof.

55. The aforementioned IMiD® and / or Cereblon E3 ligase modulating compounds include lenalidomide, pomalidomide, thalidomide, iverdamide and formula (I) 【Transformation 7】 The method according to claim 54, selected from the group consisting of compounds and their enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions and pharmaceutically acceptable salts.

56. The method according to claim 54, wherein the anti-CD20 antibody is selected from the group consisting of rituximab, obinutuzumab, ocrelizumab, and combinations thereof.

57. The method according to claim 54, wherein the chemotherapeutic agent is selected from the group consisting of cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and combinations thereof.

58. The method according to any one of claims 51 to 54, wherein the treatment for GCB-like FL comprises the therapeutically effective amount of the anti-CD20 antibody and the chemotherapeutic agent.

59. The method according to claim 58, wherein the treatment for GCB-like FL comprises the therapeutically effective amounts of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone.

60. The treatment for GCB-like FL according to any one of claims 51 to 54, comprising the therapeutically effective amount of the IMiD® and / or cereblon E3 ligase modulating compound and the anti-CD20 antibody.

61. The method according to claim 59, wherein the treatment for GCB-like FL comprises a therapeutically effective amount of rituximab and lenalidomide or its enantiomers, mixtures of enantiomers, tautomers, isotopic substitutions or pharmaceutically acceptable salts.

62. The aforementioned treatment for GCB-like FL involves the therapeutically effective dose of rituximab and formula (I) 【Transformation 8】 The method according to claim 59, comprising the compound or its enantiomers, mixtures of enantiomers, tautomers, isotope-substituted compounds or pharmaceutically acceptable salts.

63. The method according to any one of claims 50 to 62, wherein the protein expression levels of FOXP1, LMO2, CD22, and MUM1 are protein levels.

64. The method according to claim 63, wherein the protein level is measured using immunohistochemistry (IHC), multiplex ion beam imaging (MIBI), or imaging mass cytometry (IMC).

65. (i) If the protein expression level of LMO2 is strong or moderate, and the protein expression level of FOXP1 is weak or negative, (ii) If the protein expression level of LMO2 is close to (equivalently strong, moderate, or weak) the protein expression level of FOXP1, or if otherwise it has no informational value, and the protein expression level of CD22 is strong, (iii) If the protein expression level of LMO2 is close to (equivalently strong, moderate, or weak) the protein expression level of FOXP1 or otherwise has no informational value, and the protein expression level of CD22 is moderate or otherwise has no informational value, and the percentage of MUM1-positive cells in the sample is less than approximately 10%, The method according to claim 64, wherein the subject is identified as having GCB-like FL, or is identified or predicted to be highly likely to be responsive to the treatment for GCB-like FL.

66. (i) If the percentage of LMO2-positive cells in the sample is greater than approximately 50%, and the percentage of FOXP1-positive cells in the sample is less than approximately 50%, and the difference between the percentage of LMO2-positive cells in the sample and the percentage of FOXP1-positive cells in the sample is approximately 20% or more, (ii) If the difference between the percentage of FOXP1-positive cells in the sample and the percentage of LMO2-positive cells in the sample is less than approximately 20%, and the percentage of CD22 cells in the sample is greater than approximately 80%, or (iii) If the difference between the percentage of FOXP1-positive cells in the sample and the percentage of LMO2-positive cells in the sample is less than approximately 20%, the percentage of CD22-positive cells in the sample is between approximately 20% and approximately 80%, and the percentage of MUM1-positive cells in the sample is less than approximately 10%, The method according to claim 64 or 65, wherein the subject is identified as having GCB-like FL, or is identified or predicted to be highly likely to be responsive to the treatment of GCB-like FL.

67. The method according to any one of claims 1 to 65, wherein the sample is a tumor biopsy.

68. A kit for carrying out the method according to any one of claims 1 to 67, comprising (i) the gene expression level of at least one biomarker selected from the group consisting of TTC28, FOXP1, DOPEY2, IQSEC1, PTPRJ, SLA, CXXC5, PDE4B, TCF4, MPEG1, KIAA1211, SCPEP1, RASL11A, LMO2, HS2ST1, ENPP3, SH3RF1, SCIMP, CCDC138 and SHCBP1, or (ii) a drug for determining the protein expression levels of FOXP1, LMO2, CD22 and MUM1.

69. The kit according to claim 68, further comprising tools for obtaining the aforementioned sample.

70. The kit according to claim 68 or 69, further comprising instructions relating to the interpretation of the determined expression levels.

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