Compositions and methods for inhibiting DNMT1 methylation activity for reducing chemotherapy induced amplification and rearrangement in mixed lineage leukemia (MLL)

Abstract

Compositions and methods for control of DNMT1-mediated site-specific copy gains and genomic insertions associated with mixed lineage leukemia are provided.

Description

[0001]COMPOSITIONS AND METHODS FOR INHIBITING DNMT1 METHYLATION ACTIVITY FOR REDUCING CHEMOTHERAPY INDUCED AMPLIFICATION AND REARRANGEMENT IN MIXED LINEAGE LEUKEMIA (MLL) By Johnathan R. Whetstine Zach H. Gray Madison A. Honer Elena Bondarenko GRANT SUPPORT STATMENT This invention was made with government support under grant number GM144131 awarded by the U.S. National Institutes of Health. The government has certain rights in the invention. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the filing date of U.S. Provisional Application No. 63 / 676,128, filed July 26, 2024, the entire contends of which is incorporated by reference herein. INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED IN ELECTRONIC FORM The contents of the electronic sequence listing (FCCC-110-PCT.xml; Size: 13,502 bytes; and Date of Creation: July 28, 2025) is herein incorporated by reference in its entirety. FIELD The invention relates to compositions and methods for control of transient site-specific copy gains, amplifications, rearrangements, and genomic insertions associated with mixed lineage leukemia. More specifically, the invention provides methods for reducing expression and, or function of DNMT1, thereby reducing chemotherapy (e.g., topoisomerase inhibitors such as Doxorubicin) related DNA copy gains, amplifications, rearrangements, providing a new strategy for treatment of chemotherapy induced leukemia and myelodysplastic syndrome (MDS) or those associated with 5q / KDM3B LOH. BACKGROUND Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full. Chromosomal instability is a hallmark of cancer.1,2Tumor cells commonly contain structural rearrangements and copy number changes (e.g., gains / losses of chromosome arms and / or whole chromosomes and amplification / deletion of genomic regions).3While focal DNA copy gains can exist as extrachromosomal and transient, many of these events are genetically stable.4,5For example, Acute myeloid leukemia (AML) and Myelodysplastic syndrome (MDS) are characterized by the amplification and rearrangement of the MLL gene, which associates with poor outcome.6-8Rearrangement of the MLL gene results in fusions to greater than 100 partner genes, as well as noncoding regions throughout the genome,9and occur in greater than 70% of infant leukemias.10,11MLL amplification and rearrangements are also commonly observed in adult primary and therapy-associated secondary leukemias.9,12Clearly, a need exists for new targets and improved therapies for treating such cancers. SUMMARY In accordance with the present invention, a method for reducing chemotherapy-induced DNA amplification and breakpoint formation in a patient in need thereof is disclosed. In one embodiment, the method comprises administration of an effective amount of a DNMT1 inhibitor in a pharmaceutically acceptable carrier, wherein said inhibitor is administered prior to or during said chemotherapy, thereby inhibiting chemotherapy-induced DNA amplification and breakpoint formation. In another embodiment, the method can further comprise administration of at least one additional agent which increases KDM3B expression or function and, or, inhibits G9a expression or function; and, or iii) inhibits H3K9 methyltransferase expression or function. In another embodiment, the DNMT1 inhibitor is an siRNA selected from DNMT1-15 siRNA sequences: Sense: GCACCUCAUUUGCCGAAUAtt (SEQ ID NO: 1); Antisense: UAUUCGGCAAAUGAGGUGCtg (SEQ ID NO: 2); DNMT1-17 siRNA sequences: Sense: GGAUGAGAAGAGACGUAGAtt (SEQ ID NO: 3); Antisense: UCUACGUCUCUUCUCAUCCtg (SEQ ID NO: 4). In other aspects, the G9a inhibitor is selected from an siRNA GCUCUAACUGAACAACUAAtt (SEQ ID NO: 13); and CGCUGAUUUUCGAGUGUAAtt (SEQ ID NO: 14). In certain embodiments, a KDM3B agonist and G9a inhibitor are administered and act synergistically to reduce undesirable amplification. In the methods described above, the chemotherapeutic agent can be a topoisomerase II inhibitor. Such inhibitors include, without limitation, doxorubicin, daunorubicin, etoposide or Topoisomerase II alpha or beta. As noted above, the DNMT1 inhibitor can be an inhibitory nucleic acid selected from an siRNA, an antisense oligonucleotide, a shRNA, and a ribozyme having sufficient sequence homology to said DNMT1 encoding nucleic acid to reduce expression thereof in a target cell. In some aspects, the inhibitory nucleic acid comprises one or more modified nucleotides or nucleosides. In other approaches, the inhibitory nucleic acid is present in an expression vector and, or operably linked to a lipid nanoparticle. The DNMT1 inhibitor can also be a small molecule selected from decitabine, azacytidine and GSK3685032. In some embodiments, the expression levels of DNMT1 in said patient are determined prior to treatment. In other embodiments, 5q / KDM3B LOH status in said patient is determined prior to treatment. The compositions and methods of the invention can be used to advantage to treat a cancer patient. Cancers to be treated without limitation include acute myeloid leukemia, mixed lineage leukemia, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, colorectal cancer, gastric cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, liver metastases, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, thyroid carcinoma, anaplastic thyroid cancer, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, glioblastoma, and retinoblastoma. The methods for the treatment of cancer can further comprise administration of at least one anti-cancer agent selected from a BCL2 inhibitor, an alkylating agent, anti-metabolic antineoplastic agent, anti-tumor antibiotic, anti-tumor botanical, platinum compound antineoplastic agent, hormonal balance antineoplastic agent, rituximab, bevacizumab, trastuzumab, imatinib, dinoxetine, cetuximab, nilotinib, sorafenib, PD-1 inhibitor, PD-L1 inhibitor, a CTLA4 inhibitor, cyclophosphamide, ifosfamide and thiotepa, methotrexate, mercaptopurine, fluorouracil and cytarabine, bleomycin, daunorubicin, actinomycin D, mitomycin, doxorubicin and mitoxantrone, vincristine, etoposide, teniposide, paclitaxel, docetaxel, cisplatin, carboplatin, oxaliplatin, leuprolide, tamoxifen, flutamide, formestane, and arsenic trioxide, crizotinib, bosutinib, gilteritinib, amuvatinib, Sunitinib, cabozantinib, foretinib, rebastinib, celastrol and dihydroartemisinin. In certain aspects, the agents act synergistically to kill cancer cells. In yet another embodiment of the invention, a method for treating cancer in a 5q / KDM3B LOH patient in need thereof is provided. An exemplary method entails administration of an effective amount of at least one agent that inactivates KDM3B in cells and a DMT1 agonist, thereby increasing KMT2A / MLL alterations and rearrangements followed by contacting the treated cells with a topoII inhibitor, said combination acting synergistically to cause cancer cell death. KDM3B can be inactivated by genetic dCA9 mediated genetic alteration, causing increased apoptosis in targeted cells. In certain embodiments, of the method chemotherapeutic drug sensitivity is increased in said patient. In yet another aspect of the method, a G9a agonist is administered. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A- 1J. Fig. 1A) A model depicting the interplay between KDM3B, and the DNMT1 / UHRF1 / G9a complex in regulating CTCF occupancy and in turn MLL amplifications and rearrangements. (Left) KDM3B presence at MLL maintains CTCF occupancy and prevents MLL alterations. (Right) The DNMT1 / UHRF1 / G9a complex drives H3K9me1 / 2 and DNA methylation (5mc) at MLL, leading to CTCF displacement and MLL amplifications and rearrangements. Figs. 1B-1E) Analysis of TCGA LAML samples demonstrating that KMT2A amplified samples have a higher expression of DNMT1 (Fig. 1B; p value=0.036), but not DNMT3A (Fig. 1C; p value=0.8689), DNMT3B (Fig. 1D; p value=0.2104), or DNMT3L (Fig. 1E; p value=0.6412). Statistical significance was computed by Wilcoxon rank-sum test which provides a non-parametric hypothesis test on two independent samples. Fig. 1F) DNMT family enzymes transcript levels compared to control, normalized to beta-actin. Fig. 1G-1H) DNMT family overexpression screen demonstrates that only DNMT1 overexpression generates MLL copy gains (black) and breakaparts (light gray) but not CD3 copy gains (dark gray) *indicates p≤0.05. error bars are SEM. Fig. 1I) Enzymatic dead CRISPR cas9 system targeting the histone lysine methyltransferase G9a / EHMT2 with short guide RNAs to Exon 11 of the KMT2A / MLL gene to generate MLL copy gains (black) and breakaparts (light gray) but not CD3 copy gains (dark gray). * indicates p≤0.05. error bars are SEM. Fig. 1J) Enzymatic dead CRISPR cas9 system targeting the DNA methyltransferase DNMT3A with short guide RNA to Exon 11 of the KMT2A / MLL gene to generate MLL copy gains (black) and breakaparts (light gray) but not CD3 copy gains (dark gray). * indicates p≤0.05. error bars are SEM. Figures 2A- 2J. Fig. 2A) Genetic depletion of DNMT family enzymes prior to treatment with KDM3i shows that genetic depletion of DNMT1 only rescues KDM3i induced MLL copy gains and breakaparts but not DNMT3A or DNMT3B. CD3 copy gains are not impacted by genetic depletion of the DNMT family enzymes. * indicates p≤0.05. error bars are SEM. Fig. 2B) Genetic depletion of DNMT1 via siRNA prior to treatment with KDM3i shows that genetic depletion of DNMT1 modestly depletes KMT2A / MLL baseline amplifications (black) in HL60 cells. * indicates p≤0.05. error bars are SEM. Fig. 2C) Genetic co-depletion of KDM3B and DNMT1 rescue MLL copy gains (black) and breakaparts (light gray) caused by KDM3B loss. DNMT1 depletion does not impact MLL copy gains (black) or breakaparts (light gray) Genetic co-depletion of CTCF and DNMT1 do not promote CD3 copy gains (dark gray). * indicates p≤0.05. error bars are SEM. Fig. 2D) Co-inhibition of KDM3B and DNMT1 rescue MLL copy gains and breakaparts caused by KDM3B loss. DNMT1 inhibition alone does not impact MLL copy gains or breakaparts. Co-inhibition of CTCF and DNMT1 do not promote CD3 copy gains . * indicates p≤0.05. error bars are SEM. Fig. 2E) Treatment with 5-aza promotes MLL amplifications (black). Co-inhibition of 5aza and KDM3 family enzymes fully rescues MLL copy gains (black) or breakaparts (gray). * indicates p≤0.05. error bars are SEM. Fig. 2F) 5-aza dose curve on RPE cells. Fig. 2G) DNMT1i dose curve treatments on RPE cells. * indicates p≤0.05 error bars are SEM. Figs. 2H-2J. Genetic co-depletion of KDM3B and DNMT1 rescue K9me1 / 2 and CTCF at exon 11 a KMT2A / MLL via ChIP-qPCR. * indicates p≤0.05. error bars are SEM. Figures 3A -3F. Fig. 3A) Genetic depletion of DNMT1 prior to chemotherapeutic treatment with TopoII inhibitor Doxorubicin (Dox) rescues Dox induced MLL copy gains (black) and breakaparts (light gray) in RPE cells. Dox treatment does not promote CD3 copy gains (dark gray). N.S.- not significant when compared to vehicle treatment. *indicates p≤0.05. error bars are SEM. Fig. 3B) Chemical inhibition of DNMT1 prior to chemotherapeutic treatment with TopoII inhibitor Doxorubicin (Dox) rescues Dox induced MLL copy gains (black) and breakaparts (gray) in Primary AML cells. N.S.- not significant when compared to vehicle treatment. * indicates p≤0.05. error bars are SEM. Fig. 3C) DNMT1i in-vivo experiment schematic Fig. 3D) Treatment with TopoII inhibitor Doxorubicin (Dox) causes Kmt2a / Mll (light gray) copy gains in- vivo. Pretreatment of DNMT1 inhibitor prior to Dox treatment rescues Kmt2a / Mll (light gray) copy gains in-vivo. DNMT1 inhibitor does not cause Kmt2a / Mll (light gray) or control region (black) copy gains. N.S.- not significant when compared to vehicle treatment. * indicates p≤0.05. error bars are SEM. Fig. 3E) 5aza in-vivo experiment schematic. Fig. 3F) Pretreatment of 5- azacitadine inhibitor prior to Dox treatment rescues Kmt2a / Mll (black) copy gains in-vivo. * indicates p≤0.05. error bars are SEM. Figures 4A-4F. Fig. 4A) Treatment schematic (left) and DNA FISH (right) demonstrating that treatment with TET inhibitor (TETi) promotes KMT2A / MLL amplification and rearrangement events in RPE cells with no impact on nearby CD3 region. * indicates p≤0.05. error bars are SEM. Fig 4B) Treatment schematic (left) and DNA FISH (right) demonstrating that treatment with DNMT1i prior to TETi exposure rescues TETi-induced KMT2A / MLL amplification and rearrangement events in RPE cells with no impact on nearby CD3 region. * indicates p≤0.05. error bars are SEM. Fig. 4C-4D) Schematic (Fig. 4C) and DNA FISH (Fig. 4D) demonstrating that pre-treatment of dCas9 TET1 directly targeted via sgRNA to exon 11 of KMT2A / MLL fully rescues KDM3i induced KMT2A / MLL amplification and rearrangement events in RPE cells. * indicates p≤0.05. error bars are SEM. Fig. 4E-4F) Treatment schematic (Fig. 4E) and DNA FISH (Fig. 4F) demonstrating that pre-treatment of dCas9 TET1 directly targeted via sgRNA to exon 11 of KMT2A / MLL prior to 1pg dox treatment fully rescues Dox- induced KMT2A / MLL amplification and rearrangement events in RPE cells. Figures 5A-5D. Fig. 5A) RNaseH1 overexpression demonstrates that only active RNaseH1 overexpression, and not catalytic dead (D210N), generates MLL copy gains (black) and breakaparts (gray). * indicates p≤0.05. error bars are SEM. Fig. 5B) Overexpression of RNaseH rescues siDNMT1 induced KMT2A / MLL copy gains and break aparts with the clinically relevant DNA FISH probe, with no impact to the nearby CD3 region. N.S.- not significant when compared to vehicle treatment. * indicates p≤0.05. error bars are SEM. Fig. 5C Enzymatic dead CRISPR cas9 system targeting RNaseH1 or catalytically dead RNaseH1 with short guide RNAs to Exon 11 of the KMT2A / MLL gene to generate MLL copy gains (black) and breakaparts (light gray) but not CD3 copy gains (dark gray). * indicates p≤0.05. error bars are SEM. Fig. 5D) Chromatin immunoprecipitation qPCR for α-CTCF following the overexpression of wild type (WT) RNaseH1 and catalytic dead (D210n) RNaseH1 demonstrating reduction of CTCF occupancy at exon 11 of MLL / KMT2A. * indicates p≤0.05. error bars are SEM. DETAILED DESCRIPTION DNA methylation plays a significant role in MLL-rearranged leukemogenesis. The data presented herein demonstrate that the DNA methyltransferase DNMT1 is a key driver regulating maintenance and progression of leukemia. To explore how DNMT1 controls MLL alterations, the impact of DNA methylation on MLL amplification and rearrangements was assessed. DNMT1, but not DNMT3A / B activity, is required for the generation of MLL amplification and rearrangements through increasing local DNA methylation surrounding the MLL gene. Increase in DNA methylation destabilizes local RNA:DNA hybrids and suppresses the binding of CTCF, altering higher order chromatin structure and promoting MLL alterations. In mice, MLL alterations driven by the chemotherapy Doxorubicin (Dox) can be suppressed with use of a DNMT1 inhibitor, implicating DNMT1 as a promising drug target in the clinic for use in suppressing Dox-driven MLL-rearrangements, for the treatment of cancer. DEFINITIONS: The following definitions are provided to facilitate an understanding of the present invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, conventional methods of molecular biology, microbiology, recombinant DNA techniques, cell biology, and virology within the skill of the art are employed in the present invention. Such techniques are explained fully in the literature. For purposes of the present invention, "a" or "an" entity refers to one or more of that entity; for example, "a cDNA" refers to one or more cDNA or at least one cDNA. As such, the terms "a" or "an," "one or more" and "at least one" can be used interchangeably herein. It is also noted that the terms "comprising," "including," and "having" can be used interchangeably. Furthermore, a compound "selected from the group consisting of" refers to one or more of the compounds in the list that follows, including mixtures (i.e. combinations) of two or more of the compounds. The phrase "consisting essentially of" when referring to a particular nucleotide or amino acid means a sequence having the properties of a given SEQ ID NO. For example, when used in reference to an amino acid sequence, the phrase includes the sequence per se and molecular modifications that would not affect the functional and novel characteristics of the sequence. A "derivative" of a polypeptide, polynucleotide or fragments thereof means a sequence modified by varying the sequence of the construct, e.g. by manipulation of the nucleic acid encoding the protein or by altering the protein itself. "Derivatives" of a gene or nucleotide sequence refers to any isolated nucleic acid molecule that contains significant sequence similarity to the gene or nucleotide sequence or a part thereof. In addition, "derivatives" include such isolated nucleic acids containing modified nucleotides or mimetics of naturally-occurring nucleotides. The term "functional" as used herein implies that the nucleic or amino acid sequence is functional for the recited assay or purpose. For purposes of the invention, "nucleic acid", "nucleotide sequence" or a "nucleic acid molecule" as used herein refers to any DNA or RNA molecule, either single or double stranded and, if single stranded, the molecule of its complementary sequence in either linear or circular form. In discussing nucleic acid molecules, a sequence or structure of a particular nucleic acid molecule may be described herein according to the normal convention of providing the sequence in the 5' to 3' direction. With reference to nucleic acids of the invention, the term "isolated nucleic acid" is sometimes used. This term, when applied to DNA, refers to a DNA molecule that is separated from sequences with which it is immediately contiguous in the naturally occurring genome of the organism in which it originated. For example, an "isolated nucleic acid" may comprise a DNA molecule inserted into a vector, such as a plasmid or virus vector, or integrated into the genomic DNA of a prokaryotic or eukaryotic cell or host organism. Alternatively, this term may refer to a DNA that has been sufficiently separated from (e.g., substantially free of) other cellular components with which it would naturally be associated. "Isolated" is not meant to exclude artificial or synthetic mixtures with other compounds or materials, or the presence of impurities that do not interfere with the fundamental activity, and that may be present, for example, due to incomplete purification. When applied to RNA, the term "isolated nucleic acid" refers primarily to an RNA molecule encoded by an isolated DNA molecule as defined above. Alternatively, the term may refer to an RNA molecule that has been sufficiently separated from other nucleic acids with which it would be associated in its natural state (i.e., in cells or tissues). An isolated nucleic acid (either DNA or RNA) may further represent a molecule produced directly by biological or synthetic means and separated from other components present during its production. According to the present invention, an isolated or biologically pure molecule or cell is a compound that has been removed from its natural milieu. As such, "isolated" and "biologically pure" do not necessarily reflect the extent to which the compound has been purified. An isolated compound of the present invention can be obtained from its natural source, can be produced using laboratory synthetic techniques or can be produced by any such chemical synthetic route. In certain embodiments, the method of treatment effectively suppresses symptoms associated with cancer. Symptoms of vary according to the location and type of cancer being treated. In certain embodiments, symptoms of cancer include fatigue, weight loss, lumps, swelling, pain, coughing, wheezing, new or unusual growth, discoloration, and no symptoms at all. In certain embodiments, the treatment reduces the risk of relapse. In the context of a cancer, treatment or inhibition may be assessed by inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, relief of tumor-related symptoms, inhibition of tumor secreted factors, delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, increased Time To Progression (TTP), increased Progression Free Survival (PFS), increased Overall Survival (OS), among others. OS as used herein means the time from treatment onset until death from any cause. TTP as used herein means the time from treatment onset until tumor progression; TTP does not include deaths. Time to Remission (TTR) as used herein means the time from treatment onset until remission, for example, complete or partial remission. As used herein, PFS means the time from treatment onset until tumor progression or death. In one embodiment, PFS rates will be computed using the Kaplan-Meier estimates. Event-free survival (EFS) means the time from study entry until any treatment failure, including disease progression, treatment discontinuation for any reason, or death. Relapse-free survival (RFS) means the length of time after the treatment ends that the patient survives without any signs or symptoms of that cancer. Overall response rate (ORR) means the sum of the percentage of patients who achieve complete and partial responses. Complete remission rate (CRR) refers to the percentage of patients achieving complete remission (CR). Duration of response (DoR) is the time from achieving a response until relapse or disease progression. Duration of remission is the time from achieving remission, for example, complete or partial remission, until relapse. In the extreme, complete inhibition, is referred to herein as prevention or chemoprevention. In this context, the term “prevention” includes either preventing the onset of clinically evident cancer altogether or preventing the onset of a preclinically evident stage of a cancer. Also intended to be encompassed by this definition is the prevention of transformation into malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing a cancer. A “chromosomal translocation” is defined as a genome abnormality in which a chromosome breaks and either the whole or a portion of it reattaches to a different chromosome. Depending on the location of the breaks, translocations may lead to the formation of fusion genes, or may disrupt a gene or its regulatory sequences, and in this way cause gene misregulation. DNA (cytosine-5)-methyltransferase 1 (DNMT1) (GenBank accession number NM_001378627.2) is an enzyme that catalyzes the transfer of methyl groups to specific CpG sites in DNA. In humans, it is encoded by the DNMT1 gene. Dnmt1 forms part of the family of DNA methyltransferase enzymes, which consists primarily of DNMT1, DNMT3A, and DNMT3B. DNMT1 is a maintenance methyltransferase that methylates the newly synthesized CpG dinucleotides on the hemimethylated DNA during DNA replication. Dnmt1 can catalyze DNA methylation in both a de novo and maintenance context, especially at retrotransposons, where this mechanism may provide additional stability for long-term repression and epigenetic propagation throughout development. “G9a / EHMT-2” is a histone methyltransferase that specifically mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin. H3K9me represents a specific tag for epigenetic transcriptional repression by recruiting HP1 proteins to methylated histones. Also mediates monomethylation of 'Lys-56' of histone H3 (H3K56me1) in G1 phase, thereby promoting interaction between histone H3 and PCNA and regulating DNA replication. Also, weakly methylates 'Lys-27' of histone H3 (H3K27me). “CTCF” is an insulator protein, that along with cohesin, controls domain location by folding domains into loop structures. CTCF and cohesin co-occupy the same sites and physically interact as a complex. The cohesin complex is a multi-subunit ring-like structure composed of SMC1A, SMC3, RAD21, and STAG1 or STAG2 proteins and functions in the processes of anaphase sister chromatid exchange (mitotic checkpoint), DNA repair regulation, and transcription control. Agents which increase binding functions of CTCF and or RAD21 can be included with the other MLL / DKMTA amplification reducing agents described herein. Studies show that both CTCF and RAD21 are mutated in a variety of cancers and other diseases. See for example, Antony et al. (2021) Int. J. Mol. Sci. 22:(13):6788;Deardorff et al. (2012) Am. J. Human Genet. 90(6):1014-1027 and Debaugny et al., Curr Opin Genet Dev. (2020) 61:44-52 each of which are incorporated herein by reference. Common mutations in CTCF associated with disease include, for example, in order of occurrence, p.R377, p.R448, p.R457, p.H284, and p.S354. Zinc finger 1 (amino acids 260-288) and zinc finger 2, (amino acids 294-316) are also frequently mutated. Peptide mimics of these regions which stabilize or restore mutated zinc finger sequences in CTCF are also within the scope of the invention. A protein mimetic is a molecule such as a peptide, a modified peptide or any other molecule that biologically mimics the action or activity of some other protein. Protein mimetics are commonly used in drug design and discovery. Types of mimetics include without limitation, Antibody mimetics, e .g., molecules that mimic antigen binding activity of antibodies; peptidomimetics - small protein-like chains designed to mimic larger peptide and phosphomimetics - An amino acid substitution or modification which mimic the effect of protein phosphorylation. The design and generation of molecules capable of mimicking the binding and / or functional sites of proteins are used to advantage for the exploration and modulation of protein function through controlled interference with the underlying molecular interactions. Synthetic peptides are effective mimics of native protein sites because such peptides can be generated as exact copies of protein fragments and can also comprise diverse chemical modifications, which include the incorporation of a large range of non-proteinogenic amino acids as well as the modification of the peptide backbone. Apart from extending the chemical and structural diversity presented by peptides, such modifications also increase the proteolytic stability of the molecules, enhancing their utility for biological applications. Peptide mimetics of KDM3B and CTCF could provide therapeutic benefit to subjects having or being a risk for MLL. The phrase “break-apart or translocation probes” refer to probes which target two areas of a specific gene sequence. Usually, a green fluorescent label is present one end of a gene sequence and a red fluorescent label is present on the other end of the gene sequence. When the gene sequences are intact (still close together), the green and red signals will usually fluoresce as a yellow signal, known as a fusion signal. The width of the green and red signals are determined. If the green and red signals are closer than the width of one signal, they are said to be intact. When a break in the gene sequence occurs, the green and red signal will not be close together anymore and will thus appear as separate green and red signals. A “break point” is where a precise area a break occurs. The “break apart” is analyzed by the FISH technique, refers to separate areas on the gene and is typically characterized as a rearrangement. The terms “extrachromosomal DNA” or “ecDNA” refer to any DNA that is found off the chromosomes, either inside or outside the nucleus. Multiple forms of ecDNA exist and can play an important role in diseases such as cancer. ecDNA has been identified in the nuclei of various cancer cells and has been shown to cary many copies of driver oncogenes. ecDNA is considered to be a primary mechanism of gene amplification, resulting in many copies of driver oncogenes and very aggressive cancers. Proteasome inhibitors (PIs) induce the accumulation of unfolded and misfolded proteins, leading to apoptosis and cell death through ER stress, reactive oxygen species production, JNK and p53 activation, cyclin-dependent kinase inhibitors, and pro-apoptotic proteins induction. These PIs, together with other agonists (directed to KDM3B, CTCF, RAD21) and inhibitors (DNMT1i, G9a) described herein, including alkylators, immunomodulatory drugs, and monoclonal antibodies can be used to advantage to inhibit cancer growth. The terms "miRNA" and "microRNA" refer to about 10-35 nt, preferably about 15-30 nt, and more preferably about 19-26 nt, non-coding RNAs derived from endogenous genes encoded in the genomes of plants and animals. They are processed from longer hairpin-like precursors termed pre-miRNAs that are often hundreds of nucleotides in length. MicroRNAs assemble in complexes termed miRNPs and recognize their targets by antisense complementarity. These highly conserved, endogenously expressed RNAs are believed to regulate the expression of genes by binding to the 3'-untranslated regions (3'-UTR) of specific mRNAs as well as other regions on targeted mRNAs. Without being bound by theory, a possible mechanism of action assumes that if the microRNAs match 100% their target, i.e. the complementarity is complete, the target mRNA is cleaved, and the miRNA acts like a siRNA. However, if the match is incomplete, i.e. the complementarity is partial, then the translation of the target mRNA is blocked. The manner by which a miRNA base-pairs with its mRNA target correlates with its function: if the complementarity between a mRNA and its target is extensive, the RNA target is cleaved; if the complementarity is partial, the stability of the target mRNA in not affected but its translation is repressed. The term "RNA interference" or "RNAi" refers generally to a process or system in which a RNA molecule changes the expression of a nucleic acid sequence with which RNA molecule shares substantial or total homology. The term "RNAi agent" refers to an RNA sequence that elicits RNAi. An "siRNA" refers to a molecule involved in the RNA interference process for a sequence-specific post-transcriptional gene silencing or gene knockdown by providing small interfering RNAs (siRNAs) that has homology with the sequence of the targeted gene. Small interfering RNAs (siRNAs) can be synthesized in vitro or generated by ribonuclease III cleavage from longer dsRNA and are the mediators of sequence-specific mRNA degradation. Preferably, the siRNA of the invention are chemically synthesized using appropriately protected ribonucleoside phosphoramidites and a conventional DNA / RNA synthesizer. The siRNA can be synthesized as two separate, complementary RNA molecules, or as a single RNA molecule with two complementary regions. Commercial suppliers of synthetic RNA molecules or synthesis reagents include Applied Biosystems (Foster City, Calif., USA), Proligo (Hamburg, Germany), Dharmacon Research (Lafayette, Colo., USA), Pierce Chemical (part of Perbio Science, Rockford, Ill., USA), Glen Research (Sterling, Va., USA), ChemGenes (Ashland, Mass., USA) and Cruachem (Glasgow, UK). Suitable RNAs for use in the invention include without limitation: DNMT1-15 siRNA sequences: Sense: GCACCUCAUUUGCCGAAUAtt (SEQ ID NO: 1) Antisense: UAUUCGGCAAAUGAGGUGCtg (SEQ ID NO: 2) DNMT1-17 siRNA sequences: Sense: GGAUGAGAAGAGACGUAGAtt (SEQ ID NO: 3) Antisense: UCUACGUCUCUUCUCAUCCtg (SEQ ID NO: 4) RNaseH1-57 siRNA sequences: Sense: CAGACAGUAUGUUUACGAUtt (SEQ ID NO: 5) Antisense: AUCGUAAACAUACUGUCUGta (SEQ ID NO: 6) RNaseH1-58 siRNA sequences: Sense: GGGAAAGAGGUGAUCAACAtt (SEQ ID NO: 7) Antisense: UGUUGAUCACCUCUUUCCCtg (SEQ ID NO: 8) A "small nucleic acid inhibitor" refers to any sequence based nucleic acid molecule which, when introduced into a cell expressing the target nucleic acid, is capable of modulating expression of that target. siRNA, antisense, miRNA, shRNA and the like may be utilized in the methods of the invention. The term "delivery" as used herein refers to the introduction of foreign molecule (i.e., miRNA containing nanoparticle) into cells. The term "administration" as used herein means the introduction of a foreign molecule into a cell. The term is intended to be synonymous with the term "delivery". The terms "construct", “cassette”, "expression cassette", “plasmid”, “vector”, or “expression vector” is understood to mean a recombinant nucleic acid, generally recombinant DNA, which has been generated for the purpose of the expression or propagation of a nucleotide sequence(s) of interest or is to be used in the construction of other recombinant nucleotide sequences. The term “promoter” or “promoter polynucleotide” is understood to mean a regulatory sequence / element or control sequence / element that is capable of binding / recruiting an RNA polymerase and initiating transcription of sequence downstream or in a 3’ direction from the promoter. A promoter can be, for example, constitutively active, or always on, or inducible in which the promoter is active or inactive in the presence of an external stimulus. Example of promoters include T7 promoters or U6 promoters. The term “operably linked” can mean the positioning of components in a relationship which permits them to function in their intended manner. For example, a promoter can be linked to a polynucleotide sequence to induce transcription of the polynucleotide sequence. The terms "complementarity" or “complement” refer to the ability of a nucleic acid to form hydrogen bond(s) with another nucleic acid sequence by either traditional Watson-Crick or other non-traditional types. A percent complementarity indicates the percentage of residues in a nucleic acid molecule which can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 4, 5, and 6 out of 6 being 66.67%, 83.33%, and 100% complementary). "Perfectly complementary" means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence. "Substantially complementary" as used herein refers to a degree of complementarity that is at least 40%, 50%, 60%, 62.5%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100%, or percentages in between over a region of 4, 5, 6, 7, and 8 nucleotides, or refers to two nucleic acids that hybridize under stringent conditions. In some aspects, the invention provides methods for delivering one or more polynucleotides, such as or one or more vectors as described herein (e.g., encoding siRNA, antisense oligonucleotides or other type of inhibitory nucleic acid), to a host cell. In some aspects, the invention further provides cells produced by such methods, and organisms or cells comprising or produced from such cells. Conventional viral and non-viral based gene transfer methods can be used to introduce nucleic acids in mammalian cells or target tissues. Such methods can be used to administer nucleic acids encoding inhibitory compounds to cells in culture, or in a host organism. Non-viral vector delivery systems include DNA plasmids, RNA (e.g. a transcript of a vector described herein), naked nucleic acid, and nucleic acid complexed with a delivery vehicle, such as a liposome. Viral vector delivery systems include DNA and RNA viruses, which have either episomal or integrated genomes after delivery to the cell. For a review of gene therapy procedures, see Anderson, Science 256:808-813 (1992); Nabel & Felgner, TIBTECH 11:211-217 (1993); Mitani & Caskey, TIBTECH 11:162-166 (1993); Dillon, TIBTECH 11:167-175 (1993); Miller, Nature 357:455-460 (1992); Van Brunt, Biotechnology 6(10):1149-1154 (1988); Vigne, Restorative Neurology and Neuroscience 8:35-36 (1995); Kremer & Perricaudet, British Medical Bulletin 51(1):31-44 (1995); Haddada et al., in Current Topics in Microbiology and Immunology Doerfler and Bihm (eds) (1995); and Yu et al., Gene Therapy 1:13-26 (1994). Methods of non-viral delivery of nucleic acids include lipofection, nucleofection, microinjection, biolistics, virosomes, liposomes, immunoliposomes, polycation or lipid:nucleic acid conjugates, naked DNA, artificial virions, and agent-enhanced uptake of DNA. Lipofection is described in e.g., U.S. Pat. Nos. 5,049,386, 4,946,787; and 4,897,355) and lipofection reagents are sold commercially (e.g., TransfectamTMand LipofectinTM). Cationic and neutral lipids that are suitable for efficient receptor-recognition lipofection of polynucleotides include those of Feigner, WO 91 / 17424; WO 91 / 16024. Delivery can be to cells (e.g. in vitro or ex vivo administration) or target tissues (e.g. in vivo administration). The preparation of lipid:nucleic acid complexes, including targeted liposomes such as immunolipid complexes, is well known to one of skill in the art (see, e.g., Crystal, Science 270:404-410 (1995); Blaese et al., Cancer Gene Ther. 2:291-297 (1995); Behr et al., Bioconjugate Chem. 5:382-389 (1994); Remy et al., Bioconjugate Chem. 5:647-654 (1994); Gao et al., Gene Therapy 2:710-722 (1995); Ahmad et al., Cancer Res. 52:4817-4820 (1992); U.S. Pat. Nos. 4,186,183, 4,217,344, 4,235,871, 4,261,975, 4,485,054, 4,501,728, 4,774,085, 4,837,028, and 4,946,787). The use of RNA or DNA viral based systems for the delivery of nucleic acids take advantage of highly evolved processes for targeting a virus to specific cells in the body and trafficking the viral payload to the nucleus. Viral vectors can be administered directly to patients (in vivo) or they can be used to treat cells in vitro, and the modified cells may optionally be administered to patients (ex vivo). Conventional viral based systems could include retroviral, lentivirus, adenoviral, adeno-associated and herpes simplex virus vectors for gene transfer. Integration in the host genome is possible with the retrovirus, lentivirus, and adeno-associated virus gene transfer methods, often resulting in long term expression of the inserted transgene. Additionally, high transduction efficiencies have been observed in many different cell types and target tissues. The tropism of a retrovirus can be altered by incorporating foreign envelope proteins, expanding the potential target population of target cells. Lentiviral vectors are retroviral vectors that are able to transduce or infect non-dividing cells and typically produce high viral titers. Selection of a retroviral gene transfer system would therefore depend on the target tissue. Retroviral vectors are comprised of cis-acting long terminal repeats with packaging capacity for up to 6-10 kb of foreign sequence. The minimum cis-acting LTRs are sufficient for replication and packaging of the vectors, which are then used to integrate the therapeutic gene into the target cell to provide permanent transgene expression. Widely used retroviral vectors include those based upon murine leukemia virus (MuLV), gibbon ape leukemia virus (GaLV), Simian Immuno deficiency virus (SIV), human immuno deficiency virus (HIV), and combinations thereof (see, e.g., Buchscher et al., J. Virol. 66:2731-2739 (1992); Johann et al., J. Virol. 66:1635-1640 (1992); Sommnerfelt et al., Virol. 176:58-59 (1990); Wilson et al., J. Virol. 63:2374-2378 (1989); Miller et al., J. Virol. 65:2220-2224 (1991); PCT / US94 / 05700). In applications where transient expression is preferred, adenoviral based systems may be used. Adenoviral based vectors are capable of very high transduction efficiency in many cell types and do not require cell division. With such vectors, high titer and levels of expression have been obtained. This vector can be produced in large quantities in a relatively simple system. Adeno-associated virus ("AAV") vectors may also be used to transduce cells with target nucleic acids, e.g., in the in vitro production of nucleic acids and peptides, and for in vivo and ex vivo gene therapy procedures (see, e.g., West et al., Virology 160:38-47 (1987); U.S. Pat. No. 4,797,368; WO 93 / 24641; Kotin, Human Gene Therapy 5:793-801 (1994); Muzyczka, J. Clin. Invest. 94:1351 (1994). Construction of recombinant AAV vectors are described in a number of publications, including U.S. Pat. No. 5,173,414; Tratschin et al., Mol. Cell. Biol. 5:3251-3260 (1985); Tratschin, et al., Mol. Cell. Biol. 4:2072-2081 (1984); Hermonat & Muzyczka, PNAS 81:6466-6470 (1984); and Samulski et al., J. Virol. 63:03822-3828 (1989). Packaging cells are typically used to form virus particles that are capable of infecting a host cell. Such cells include 293 cells, which package adenovirus, and ψ2 cells or PA317 cells, which package retrovirus. Viral vectors used in gene therapy are usually generated by producing a cell line that packages a nucleic acid vector into a viral particle. The vectors typically contain the minimal viral sequences required for packaging and subsequent integration into a host, other viral sequences being replaced by an expression cassette for the polynucleotide(s) to be expressed. The missing viral functions are typically supplied in trans by the packaging cell line. For example, AAV vectors used in gene therapy typically only possess ITR sequences from the AAV genome which are required for packaging and integration into the host genome. Viral DNA is packaged in a cell line, which contains a helper plasmid encoding the other AAV genes, namely rep and cap, but lacking ITR sequences. The cell line may also be infected with adenovirus as a helper. The helper virus promotes replication of the AAV vector and expression of AAV genes from the helper plasmid. The helper plasmid is not packaged in significant amounts due to a lack of ITR sequences. Contamination with adenovirus can be reduced by, e.g., heat treatment to which adenovirus is more sensitive than AAV. As used herein, the phrase "effective amount" of a compound or pharmaceutical composition refers to an amount sufficient to modulate tumor growth or metastasis in an animal, especially a human, including without limitation decreasing tumor growth or size or preventing formation of tumor growth in an animal lacking any tumor formation prior to administration, i.e., prophylactic administration. Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" refers, for example, to a diluent, adjuvant, excipient, auxiliary agent or vehicle with which an active agent of the present invention is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. A pharmaceutical composition of the present invention can be administered by any suitable route, for example, by injection, by oral, pulmonary, nasal or other forms of administration. In general, pharmaceutical compositions contemplated to be within the scope of the invention, comprise, inter alia, pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and / or carriers. Such compositions can include diluents of various buffer content (e.g., Tris HCl, acetate, phosphate), pH and ionic strength; additives such as detergents and solubilizing agents (e.g., Tween 80, Polysorbate 80), anti oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimersol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol); incorporation of the material into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc., or into liposomes. Such compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of components of a pharmaceutical composition of the present invention. See, e.g., Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) pages 14351712 which are herein incorporated by reference. A pharmaceutical composition of the present invention can be prepared, for example, in liquid form, or can be in dried powder, such as lyophilized form. Particular methods of administering such compositions are described infra. In yet another embodiment, a pharmaceutical composition of the present invention can be delivered in a controlled release system, such as using an intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In a particular embodiment, a pump may be used [see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)]. In another embodiment, polymeric materials can be used [see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Press: Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley: New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105 (1989)]. In yet another embodiment, a controlled release system can be placed in proximity of the target tissues of the animal, thus requiring only a fraction of the systemic dose [see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115138 (1984)]. In particular, a controlled release device can be introduced into an animal in proximity of the site of inappropriate immune activation or a tumor. Other controlled release systems are discussed in the review by Langer [Science 249:15271533 (1990)]. As used herein the term "biomarker" refers to a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. As used herein, the terms "modulate", "modulating" or "modulation" refer to changing the rate at which a particular process occurs, inhibiting or promoting a particular process, reversing a particular process, and / or preventing the initiation of a particular process. Accordingly, if the particular process is tumor growth or metastasis, the term "modulation" includes, without limitation, decreasing the rate at which tumor growth and / or metastasis occurs; inhibiting tumor growth and / or metastasis; reversing tumor growth and / or metastasis (including tumor shrinkage and / or eradication) and / or preventing tumor growth and / or metastasis. A compound that increases a known activity, e.g., tumor growth or metastasis, is an “agonist”. One that decreases, or prevents, an undesirable malignant phenotype is an “antagonist” or “inhibitor”. As used herein, the terms "tumor", "tumor growth" or "tumor tissue" can be used interchangeably, and refer to an abnormal growth of tissue resulting from uncontrolled progressive multiplication of cells and serving no physiological function. A solid tumor can be malignant, e.g. tending to metastasize and being life threatening, or benign. Examples of solid tumors that can be treated or prevented according to a method of the present invention include sarcomas and carcinomas such as, but not limited to: fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, colorectal cancer, gastric cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, liver metastases, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, thyroid carcinoma such as anaplastic thyroid cancer, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma such as small cell lung carcinoma and non-small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, glioblastoma, and retinoblastoma. The phrase “treatment induced cancer” refers to a new cancer or tumor in a patient with a preexisting cancer that is developed in response to treatment of the preexisting cancer. “Chemo- induced cancer” or “chemotherapy induced cancer” refers to a treatment induced cancer that was developed in response to chemotherapy treatment. In certain embodiments of any of the preceding methods for the treatment of cancer, the method may include administering a BCL2 inhibitor. In another aspect, the chemotherapeutic agent is selected from alkylating agent, anti-metabolic antineoplastic agent, anti-tumor antibiotic, anti-tumor botanical, platinum compound antineoplastic agent, hormonal balance antineoplastic agent, miscellaneous antineoplastic agent, rituximab, bevacizumab, trastuzumab, imatinib, dinoxetine, cetuximab, nilotinib, sorafenib, PD-1 inhibitor, PD-L1 inhibitor and CTLA4 inhibitor, cyclophosphamide, ifosfamide and thiotepa, methotrexate, mercaptopurine, fluorouracil and cytarabine, bleomycin, daunorubicin, actinomycin D, mitomycin, doxorubicin and mitoxantrone, vincristine, etoposide, teniposide, paclitaxel, docetaxel, cisplatin, carboplatin, oxaliplatin, leuprolide, tamoxifen, flutamide, formestane, and arsenic trioxide. Furthermore, in any one of the preceding methods, the AXL inhibitor can be at least one of R428 / BGB 324 / bemcentinib, TP-0903, RXDX-106 / CEP-40783, crizotinib, bosutinib, gilteritinib, amuvatinib, and Sunitinib, cabozantinib, foretinib, rebastinib, celastrol, dihydroartemisinin. As used herein, the phrase “chromosomal instability” refers to a higher than normal rate of mis-segregation of chromosomes or parts of chromosomes during mitosis due to defective cell cycle quality control mechanisms, resulting in copy number alterations (CNAs) or aneuploidy. The phrase “gene amplification” or “copy number amplification” or “DNA copy gain” refers to an increase in the number of copies of a gene sequence. In certain embodiments, these phrases refer to any number of copies greater than diploid. There may also be an increase in the RNA and protein made from that gene. Gene amplification is common in cancer cells, and some amplified genes may cause cancer cells to grow or become resistant to anticancer drugs. Gene amplification of oncogenes on ecDNA is a frequent event in cancer. “Epigenetic state” or “Epigenetic phenomena”, as used herein, means changes produced in gene expression or other DNA-dependent processes caused by mechanisms other than changes in the underlying DNA sequence. For example, methylation of cytosines (Cs) or histone modifications can affect expression of a gene. These molecular modifications of the DNA are often called "epigenetic marks." For example, increased or decreased methylation of Cs in a genome are part of normal biology but can also be associated with disease. In a similar fashion, post translational modifications (PTMs) occur on histones and impact DNA-dependent processes. As used herein, "epigenetic state" refers to a gene or region in a genome that reflects particular epigenetic phenomena. For example, in a particular disease cohort, a gene can be found that causes disease through multiple mechanisms, including, but not limited to, impairment of protein function by a SNV, deletion of the gene via a CNV, little or no expression of the gene due to a change in the epigenetic state of the gene itself and / or regulatory region(s) in the genome controlling expression of the gene. An "inhibitor" (interchangeably termed "antagonist") of a polypeptide of interest (e.g., DNMT1) is an agent that interferes with activation or function of the polypeptide of interest, e.g., partially or fully blocks, inhibits, or neutralizes a biological activity mediated by a polypeptide of interest. For example, an antagonist of DNMT1 may refer to any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity mediated by DNMT1 (e.g., methylation activity). Examples of inhibitors include antibodies; ligand antibodies; small molecule antagonists; antisense and inhibitory RNA (e.g., siRNA) molecules. Cytidine analogs decitabine or azacytidine, have demonstrated clinical benefit in hematologic malignancies. These nucleoside analogs are incorporated into replicating DNA where they inhibit DNA cytosine methyltransferases DNMT1, DNMT3A and DNMT3B through irreversible covalent interactions. These agents induce notable toxicity to normal blood cells thus limiting their clinical doses. GSK3685032, a newly discovered potent first-in-class DNMT1- selective inhibitor has been shown via crystallographic studies to compete with the active-site loop of DNMT1 for penetration into hemi-methylated DNA between two CpG base pairs. GSK3685032 induces robust loss of DNA methylation, transcriptional activation and cancer cell growth inhibition in vitro. Exhibiting enhanced in vivo tolerability compared with decitabine, GSK3685032 can be used to advantage to for inducing tumor regression and improved survival in mouse models of acute myeloid leukemia. siRNAs described above “modified nucleotides”. These are nucleotides comprising non- naturally occurring moieties that confer increased nuclease resistance or thermodynamic stability during hybridization as compared with a polynucleotide or polyribonucleotide that differs from the inhibitory nucleic acid only by having a natural nucleotide in place of the modified nucleotide. In certain embodiments, the ribose moiety of a nucleotide is modified with an extra bridge connecting the 2′ oxygen and 4′ carbon. Numerous chemical modifications are commonly used for the synthesis of oligonucleotides for a variety of reasons. For example, to increase the phosphate backbone's stability, adjust duplex stability, change the oligonucleotide's conformation, or increase its ability to penetrate a lipid bilayer. Modified sugar moieties are also being incorporated into therapeutic oligonucleotides. Changing the sugar moiety generally increases nuclease resistance and binding affinity to a complementary target. “Bridged nucleic acid” (“BNA”) refers to 2′-O,4′-C-methylene-modified nucleic acids. In preferred embodiments, BNA, where the 2′ oxygen and 4′ carbon are bridged by a methylene group are used. In other approaches, 2′-O,4′-C-ethylene-bridged nucleic acids (ENA), the 2′ oxygen and 4′ carbon are bridged by an ethylene group. Other examples of BNA can include, but are not limited to, 2′,4′-BNANC[NH], 2′,4′-BNANC[NMe], and 2′,4′-BNANC[NBn], (s)-cEt (S- constrained Ethyl). tcDNA (tricycloDNA) modifications can also be used to constrain nucleotides. “Locked nucleic acid nucleotide” (“LNA nucleotide”) as used herein, refers to a modified RNA nucleotide that provides the polynucleotide with greater thermodynamic stability during hybridization as compared with a polynucleotide that differs from the LNA only by having a natural ribonucleotide in place of the modified RNA nucleotide. In certain embodiments, the ribose moiety of a modified RNA nucleotide is modified with an extra bridge connecting the 2′ oxygen and 4′ carbon. LNA nucleotides can comprise any type of extra bridge between the 2′-O and 4′-C of the RNA that increases the thermodynamic stability of the duplex between the LNA and its complement. Other 2′-O-modified nucleotides, such as 2′-O-Me, demonstrate greater stability, as well. Oligonucleotide backbone configurations that demonstrate particularly high binding affinities to the target (measured by melting temperature or Tm) are preferred for implementing the steric hindrance mechanism. BNA, LNA, FANA, 2′-fluoro, 2’-O-methoxyethyl (2’-MOE), 2’-NH2, 2’-F-RNA, morpholino and piperazine containing backbones are particularly well suited for this purpose. Other modifications on the oligonucleotide ribose include, are not limited to, FHNA (Fluoro Hexitol Nucleic Acid), (s)-5’-C-methyl, UNA (Unlocked Nucleic Acid), 4’-thio-RNA, cyclohexene nucleic acid. Modified backbone linkages are sometimes used instead of phosphodiester linkage to minimize oligonucleotide degradation by nucleases. Some examples include, are not limited to, phosphorothioate, boranophosphonate, phosphoramidate, methyl phosphonate, (SC5’ Rp)-α,β- CNA (Dioxaphosphorinane-Constrained Nucleic Acid), PNA (Peptide Nucleic Acid), PMO (Phosphorodiamidate Morpholino Oligonucleotide), phosphoryl guanidine. 5’ modifications to increase phosphate stability include, are not limited to, E-VP ((E)-VinylPhosphonate), 5’ methyl phosphonate, 5’-phosphorothioate, (s)-5’-methyl with phosphate, 5’-methoxy. 3’ modifications to increase phosphate stability include, are not limited to, 2-hydroxyethylphosphate AND, 3’-ddc (dideoxyCytosine), 3’-amino. Base modifications to improve 3’ stability include, are not limited to, 2’-thio-dT. The generation of oligonucleotides with mixed linkages such as boranophosphate and phosphate linkages has been accomplished by several solid phase methods including one involving the use of bis(trimethylsiloxy)cyclododecyloxysilyl as the 5′-0-protecting group (Brummel and Caruthers, Tetrahedron Lett 43: 749, 2002). In another example the 5′-hydroxyl is initially protected with a benzhydroxybis-(trimethylsilyloxy)silyl group and then deblocked by Et3N:HF before the next cycle (McCuen et al., J Am Chem Soc 128: 8138, 2006). This method can result in a 99% coupling yield and can be applied to the synthesis of oligos with pure boranophosphate linkages or boranophosphate mixed with phosphodiester, phosphorothioate, phosphorodithioate or methyl phosphonate linkages. The boranophosphorylating reagent 2-(4-nitrophenyl)ethyl ester of boranophosphoramidate can be used to produce boranophosphate linked oligoribonucleotides This reagent readily reacts with a hydroxyl group on the nucleosides in the presence of 1H- tetrazole as a catalyst. The 2-(4-nitrophenyl)ethyl group can be removed by 1,4- diazabicyclo[5.4.0]undec-7-ene (DBU) through beta-elimination, producing the corresponding nucleoside boranomonophosphates (NMPB) in good yield. Nucleobase modifications to increase binding affinity include, are not limited to, 5’- methylcytidine, 5-methyluridine (ribothymidine), and abasic RNA. The phrase “MLL inhibitor”, “DNMT1 inhibitor”, MLL / DNMT1 inhibitor” or “Mixed Lineage Leukemia inhibitor” refers to any compound naturally occurring or synthesized, having the ability of inhibiting amplification caused by doxorubin in the presence of active DNMT1 methylation. The phrase “G9a inhibitor” refers to any compound natural occurring or synthesized, having the ability of inhibiting G9a activity, stability or expression. A G9a inhibitor is for example UNC0642, available on the world wide web at apexbt.com / unc- 0642.html?gclid=EAIaIQobChMI-4Ku0tW1-AIVIxTUAR3f_gpZEAAYASAAEg KST_D_BwE. Additional G9a inhibitors are known to those skilled in the art. Also see Vedadi et al. (2011) Nat. Chem. Biol.7(8):566-574. In other embodiments, the G9a inhibitor is an siRNA. In certain embodiments, the siRNA is selected from GCUCUAACUGAACAACUAAtt (SEQ ID NO: 13); and CGCUGAUUUUCGAGUGUAAtt (SEQ ID NO: 14). The term "drug response" as used herein, means any biological response in an organism that is the result of exposure to the drug. Drug responses can be favorable, such as when a patient's disease is eradicated by treatment with the drug, or unfavorable, such as when a patient enters a coma upon treatment with a drug. The following materials and methods are provided to facilitate the practice of the present invention. Cell Culture Retinal pigment epithelial (RPE) cells were cultured in DMEM-high glucose (Sigma) media supplemented with 10% heat-inactivated fetal bovine serum (FBS), 100U / ml penicillin, 100µg / ml streptomycin, and 2mM L-glutamine. HL60 cells were cultured in RPMI 1640 media supplemented with 20% heat-inactivated FBS, 100U / ml penicillin, 100µg / ml streptomycin and 2mM L-glutamine. Cell line identities were authenticated by short tandem repeat analysis and Mycoplasma tested using the MycoAlert Detection Kit (Lonza, LT07-218). Human primary patient-derived AML cells were obtained, generated and maintained as described previously1and as follows: Primary patient-derived AML cells were maintained on 30 Gy-irradiated OP9 feeder layer cells in complete in Iscove’s modified Dulbecco’s medium (IMDM; Thermo Fisher Scientific, Waltham, MA) containing 20% fetal bovine serum (Corning Premium FBS), 100 IU / ml penicillin, 100 μg / ml streptomycin, 50 µM 2-mercaptoethanol and supplemented with AML-maintaining cytokines (50 ng / ml SCF, 20 ng / ml GM-CSF, 50 ng / ml FLT3 ligand, 20 ng / ml IL-3, 20 ng / ml IL-6, and 20 ng / ml G-CSF). Transfection Procedure for RPE cells Cells were plated in 10 cm cell culture dishes and allowed to adhere for 16-20 hours. Cell culture medium was removed, cells were rinsed with phosphate buffered saline (PBS) and then replaced with OPTI-MEM medium (Life Technologies) prior to siRNA transfections (5nM- 10nM / transfection). Transfections were changed to complete cell culture media after 4 hrs of transfection, and cells were collected 72 hrs post transfection. For Figure 2C, siRNAs were transfected at the same time. Transient overexpression transfections with 1-2µg of plasmid were performed using Lipofectamine 3000 transfection reagent and P3000 reagent (Life Technologies) in OPTI-MEM medium for 4 hrs, followed by changing to complete DMEM media for 24 hrs before collection. Silencer select negative controls and siRNAs were purchased from Life Technologies. Transient dCas9 transfections (Figure 1I, 1J, and 4C-4F) with 0.75µg of dCas9 plasmid and 0.75µg sgRNA were performed using, Lipofectamine 3000 transfection reagent and P3000 reagent (Life Technologies) in OPTI-MEM medium for 4 hrs, followed by changing to complete DMEM media for 24 hrs before collection. Negative controls and sgRNA were purchased from IDT. Transfection procedure for HL60 cells HL60 were transfected using Neon System (Invitrogen) following manufacturer’s instructions. 500,000 cells were mixed with 10nM siRNA constructs in 10µl of supplied buffer. Cell mixture was loaded in Neon syringe and submerged in electrode buffer. 1 pulse of 1350 mV at 35ms was applied. Cells were immediately transferred into fresh media in 6 well plates and allowed to grow for 72 hours. RNA extraction and quantitative real-time PCR Cells were washed and collected by trypsinization after two PBS washes. Cell pellet was resuspended in Qiazol reagent (QIAGEN) for lysis and stored at -80°C before further processing. Total RNA was extracted using miRNAeasy Mini Kit (QIAGEN) with an on-column DNase digestion according to the manufacturer’s instructions. RNA was quantified using NanoDrop 2000 or One (Thermo Scientific). Single strand cDNA was prepared using Super Script IV first strand synthesis kit (Invitrogen) using random hexamers. Expression levels were analyzed using FastStart Universal SYBR Green Master (ROX) (Roche) according to the manufacturer’s instructions on a LightCycler 480 PCR machine (Roche) or QuantStudio 5 Real-time PCR machine (Applied Biosystems). Samples were normalized to β-actin. DNA Fluorescent In Situ Hybridization (FISH) The FISH protocol was performed as described previously in2. Briefly, cell suspensions were fixed in ice-cold methanol:glacial acetic acid (3:1) solution for a minimum of four hours, before being centrifuged onto 8 Chamber Polystyrene vessel tissue culture treated glass slides (Falcon, Fisher Scientific) at 900rpm. The slides were air-dried and incubated in 2X SSC buffer for 2 min, followed by serial ethanol dilution (70%, 85% and 100%) incubations for 2 min each, for a total of 6 min. Air-dried slides were hybridized with probes that were diluted in appropriate buffer overnight at 37°C. The slides were washed the next day for 3 to 4 mins in appropriate wash buffers at 69°C with 0.4X SSC for Cytocell probes, Agilent Buffer1 for Agilent probes, or 0.4X SSC + 0.3% NP-40 for Empire Genomic probes followed by washing in 2X SSC with 0.05% Tween-20 (Cytocell probes), Agilent Buffer 2 (Agilent) or 2X SSC+0.1% NP-40 (Empire). The slides were incubated in 1mg / mL DAPI solution made in 1% BSA-PBS, followed by a final 1X PBS wash. After the wash, the slides were mounted with ProLong Gold antifade reagent (Invitrogen). FISH images were acquired using an Olympus IX81 or Olympus IX83 spinning disk microscope at 40X magnification and analyzed using Slidebook 6.0 software. A minimum of 20 z-planes with 0.5µm step size was acquired for each field. Copy number gains for MLL1,11C, NMYC / LAF4 were scored in RPE cells as three or more foci. For MLL break apart probe, copy gains were scored as 3 or more foci for the N terminus flanking probe (green) and C terminus flanking probe (red). Complete separation of red and green probe with no overlap was called break apart for the MLL locus, TCF3 locus and any other locus FISHed with dual break apart probe. A minimum of 200 nuclei are scored for each independent experiment unless otherwise specified. Extended list of probes used are provided in the key resource table. Drug Treatment Conditions KDM3i was synthesized for these studies. For Figure 2A, 1.8x105RPE cells were plated in 10cm tissue culture plates. Cells were allowed to adhere to the plate for a minimum of 24 hrs before transfection as described previously. 60 hours post-transfection, KDM3i (dissolved in DMSO) was supplemented to media at 25nM, and cells were collected 12 hours later. For Figures 2D-2E, 1.5x105RPE cells were plated in 10cm tissue culture plates. Cells were allowed to adhere to the plate for a minimum of 24 hrs before DNMT1i (GSK3685032; Figure 2D) or 5-aza (Figure 2E) were supplemented to the media, both at 100nM. 60 hours later, KDM3i (dissolved in DMSO) was supplemented to media at 25nM, and cells were collected 12 hours later. For Figure 3A, 1.8x105RPE cells were plated in 10cm tissue culture plates. Cells were allowed to adhere to the plate for a minimum of 24 hrs before transfection as described previously. 48 hours post-transfection, Doxorubicin was supplemented to media at 1pg / μl, and cells were collected 24 hours later. For Figure 3B, 1.5x105RPE cells were plated in 10cm tissue culture plates. Cells were allowed to adhere to the plate for a minimum of 24 hrs before DNMT1i was supplemented to the media at 100nM. 48 hours later, Doxorubicin was supplemented to the media at 1pg / μl, and cells were collected 24 hours later. For Figures 4A-4B, 1.5x105RPE cells were plated in 10cm tissue culture plates. Cells were allowed to adhere to the plate for a minimum of 24 hrs before TETi (C35; Figure 4A) at 1uM or DNMT1i (Figure 4B) at 100nM were supplemented to the media. 48 hours later, TETi was supplemented to media at 1uM, and cells were collected 24 hours later. For Figures 4C-4F, 4.0x105RPE cells were plated in 10cm tissue culture plates. Cells were allowed to adhere to the plate for a minimum of 48 hrs before dcas9 TET1 transfection as described above. KDM3i (Figure 4C-4D) was supplemented to media at 25nM, and cells were collected 12 hours later. Dox (Figure 4E-4F) was supplemented to media at 25nM, and cells were collected 12 hours later. Chromatin Immunoprecipitation Sonication of chromatin was done with the Qsonica Q800R2 system (Qsonica). RPE cells were seeded in 10cm plates. At ~80% confluence, crosslinking of the cells was done by adding 1% formaldehyde to the media for 13 min at 37°C and stopped with 0.125M glycine, pH2.5. Plates were washed with ice cold PBS and scraped off, followed by centrifugation at 800 rpm for 2 min at 4°C. The pellet was resuspended in cellular lysis buffer (5mM PIPES pH8.00, 85mM KCl, 0.5% NP40) supplemented with protease inhibitors, incubated 5 min on ice and centrifuged at 800 rpm, 2 min at 4°C. The pellet was resuspended in nuclear lysis buffer supplemented with protease inhibitors (NLB, 50mM Tris, pH 8.0, 1.0% SDS, or 0.2% SDS for CTCF ChIP). Chromatin was sonicated at 70% amplitude 15sec on 45sec off setting for 35 min or 45 min for CTCF ChIP. 5 μL of chromatin was RNase treated, and reverse cross-linked at least 4 hrs at 65°C in presence of proteinase K. DNA was isolated by phenol:chloroform extraction and checked on 1.3% agarose gel for a smear below 300bp. Chromatin was precleared by centrifugation at 14,000rpm for 10min at 4°C. Chromatin concentration was then quantified on a NanoDrop One. For each IP, 1-10μg of chromatin was immunoprecipitated with 0.2-2μg of antibody in dilution IP buffer (16.7mM Tris pH 8.0, 1.2mM EDTA pH 8.0, 167mM NaCl, 0.2% or 0.1% SDS, 0.24% Triton-X-100 or 1.84% for CTCF ChIP) at 4°C overnight. % SDS for dilution IP depended on % SDS used in Nuclear Lysis Buffer. Final concentration for IP was always 0.2% SDS. Chromatin was precleared for 2 hrs each with protein A agarose and magnetic protein A or protein G beads (Invitrogen; to match antibody isotype) rotating at 4°C before immunoprecipitation. The immunoprecipitated material was washed 2 times in dilution IP buffer, 1 time in TSE buffer (20mM Tris pH 8.0, 2mM EDTA pH8.0, 500mM NaCl, 1% Triton X-100, 0.1% SDS), 1 time in LiCl buffer (100mM Tris pH 8.0, 500mM LiCl, 1% deoxycholic acid, 1% NP40) and 2 times in TE (10mM Tris pH 8.0, 1mM EDTA pH 8.0) before elution in elution buffer (50mM NaHCO3, 140mM NaCl, 1% SDS) with RNase treatment, followed by 10µg proteinase K at 1 hr 55°C 1000 rpm. The samples were removed from beads and reverse cross- linked at 65°C for 4 hrs. Immunoprecipitated DNA was purified using either PCR purification columns (Promega) or AMPureXP beads. All the ChIPs were performed with at least two independent chromatin preparations from two independent siRNAs or two independent RPE cell lines. Antibodies used for ChIP are as follows: H3K9me1 Abcam ab8896-100, H3K9me2 Abcam ab1220, H3K9me3 Abcam ab8898, CTCF (D31H2) Cell Signaling #3418. ChIP sequencing libraries were prepped using the TruSeq ChIP Sample Preparation kit (Illumina). Libraries were single-end sequenced (75 cycles) using a NextSeq500 (Illumina). ChIP-qPCR was performed with 1µl of ChIP DNA with the following primers: (KMT2A Ex11) Forward - 5’- TCTGTCACGTTTGTGGAAG-3’ (SEQ ID NO: 9), Reverse - 5’- GCCCAGCTGTAGTTCTATTAC-3’(SEQ ID NO: 10). ChIP-qPCR was performed with 1µl of ChIP DNA with the following primers: (KMT2A CTCF flanking site) Forward - 5’- CAGCCAGAATCCCAGTAGA-3’(SEQ ID NO: 11), Reverse 5’- CTTTCAGAGGAGGCTACAGA-3’(SEQ ID NO: 12). In vivo Drug Treatments For the DNMT1i in vivo combination treatment, Doxorubicin (Selleckchem) was solubilized in saline and GSK3685032 was solubilized in 10% Captisol. 14 male and 16 female mice of B6129SF1 / J strain (The Jackson Laboratory 101043) were assigned into 4 groups treated with: i) vehicle (n=8, four males, four females); ii) 8 doses of GSK3685032 (twice daily, subcutaneous, 45mg / kg) (n=8, four males, four females); iii) 3 doses of Doxorubicin (daily i.v. 1.5 mg / kg) (n=8, four males, four females); iv) 8 doses of GSK3685032 with 3 doses of Doxorubicin implemented into the treatment starting day 2 (n=6, two males, four females). For the 5-aza in vivo combination treatment, Doxorubicin (Selleckchem) was solubilized in saline and 5aza was solubilized in saline. 14 male and 16 female mice of B6129SF1 / J strain (The Jackson Laboratory 101043) were assigned into 4 groups treated with: i) vehicle (n=8, four males, four females); ii) 4 doses of 5aza (once daily, subcutaneous, 5mg / kg) (n=8, four males, four females); iii) 3 doses of Doxorubicin (daily i.v. 1.5 mg / kg) (n=8, four males, four females); iv) 4 doses of 5aza with 3 doses of Doxorubicin implemented into the treatment starting day 2 (n=6, two males, four females).The day after the final treatment, mice were euthanized, and the cells were isolated from spleen for double blinded examination by Kmt2a and control FISH (Control 9). The following examples are provided to illustrate certain embodiments of the invention. They are not intended to limit the invention in any way. EXAMPLES We recently discovered a role of histone modifying enzymes in regulating MLL amplification and rearrangements.4Increased levels of histone 3 lysine 9 mono- and di- methylation (H3K9me1 / 2) promotes MLL amplification and rearrangements, which was driven by loss of the H3K9me1 / 2 demethylase KDM3B and prevented by loss of the H3K9me1 / 2 methyltransferase G9a. This study demonstrated that loss of KDM3B led to a reduction in CTCF binding at MLL, and increased propensity of the region to undergo alterations. Furthermore, the chemotherapy Doxorubicin (Dox), promotes MLL amplification and rearrangements, which could be prevented through chemically inhibiting the driver of these alterations, G9a.4Previously G9a was shown to interact with the DNA methyltransferase DNMT1, maintaining H3K9 and DNA methylation levels during replication.13DNMT1, the sole maintenance mammalian DNA methyltransferase, is highly expressed in AML and is required for AML development.14,15We previously reported that site-specific DNA copy gains occur exclusively during S phase,16-18suggesting a role for DNA replication in promoting genomic amplifications and rearrangements. These studies prompted us to assess whether DNMT1-dependent DNA methylation is required to promote MLL amplification and rearrangements. Here, we demonstrate that DNMT1, but not the de novo DNA methyltransferases DNMT3A or DNMT3B are required for MLL amplification and rearrangements by DNA fluorescent in situ hybridization. We further establish that DNMT1 overexpression in tumors associates with MLL copy gains, which was recapitulated in vitro. Furthermore, inhibiting DNMT1 though chemical inhibition or depletion via siRNAs, the MLL alterations were prevented when KDM3B was reduced or inhibited. The reduced CTCF occupancy observed with KDM3B reduction was also rescued when DNMT1 was depleted, which emphasized a role in DNA methylation in controlling the amplifications and rearrangements. The DNA methylation changes occur in regions that flank the CTCF site, which were also DNMT1-dependent. These altered methylation events were at regions shown to be enriched in RNA:DNA hybrids. Therefore, we have established an intricate balance in H3K9me1 / 2, DNA methylation and DNA structure in controlling the ability of the MLL locus to undergo alterations. These mechanisms were further leveraged in mice treated with Doxorubicin (Dox), which promotes MLL amplification. Upon inhibiting DNMT1, Dox-induced MLL alterations were prevented in vivo. Therefore, the ability to modulate the lysine and DNA methylation state are critical parameters in reducing the topoisomerase induced MLL alterations observed with treatment. DNMT1 is required to promote MLL amplification and rearrangements. DNMT1 and G9a / EHMT2 have been shown to function together to ensure proper DNA and histone methylation during replication.3The regulation of H3K9me1 / 2 by G9a and lysine demethylase KDM3B were shown to control CTCF binding, and in turn, the site-specific DNA amplification and rearrangement of MLL. However, the exact contribution to the CTCF binding modulation was not elucidated. DNA methylation has been implicated as a critical parameter in CTCF occupancy control. Therefore, we hypothesize that increased DNMT1 expression or targeting of DNA methylation to the MLL locus is associated with the site-specific control of the MLL amplifications and rearrangements (Fig. 1A). To first confirm this relationship in cancer, gene expression levels of DNMT1, DNMT3A, DNMT3B, and DNMT3L in The Cancer Genome Atlas (CGA) AML (LAML) samples were assessed for MLL / KMT2A amplifications. Only increased expression of DNMT1 positively correlated with KMT2A amplified samples compared to DNMT3A, DNMT3B, or DNMT3L (p= 0.0360; Figs. 1B-1E). To assess whether increased DNMT expression promotes selective amplification and rearrangement of KMT2A / MLL, the immortalized retinal pigment epithelial (RPE) cells were transiently overexpressed with the DNMT family members before being validated for overexpression and MLL alterations (Fig. 1F). These cells have been previously established to be ideal for assessing DNA amplification and rearrangement events as they are near diploid, have a stable genome, and do not harbor any cancer mutations.2,4-9A DNA FISH probe against the KMT2A gene (Figure 1G; noted in red and green) and a nearby control region (noted in grey) were used to evaluate site-specific DNA copy gains and rearrangement events. Copy number gain evaluation for each FISH probe was measured in percentages as previously described.2,9-12The most significant alteration was observed upon DNMT1 overexpression with minimal changes with the other DNMTs (Fig. 1H). We then tested whether directly targeting H3K9 and DNA methylation at the KMT2A / MLL locus would be sufficient to drive these MLL events. Using an enzymatically inactive CRISPR- dcas9 system, EHMT2 / G9a was directed to exon 11, the breakpoint cluster region of the MLL locus, and an additional control region (Figure 1I, upper schematic). Targeting G9a-dCas9 to exon 11 at the KMT2A / MLL locus, but not at the control region, significantly increased MLL amplification and rearrangement events (Figure 1I). We then assessed the impact of DNA methylation at the locus by using the same guides but targeting DNMT3A-dCas9, which promoted site selective amplification and rearrangement events (Figure 1J). DNMT3A overexpression without targeting had a modest impact, suggesting the increased impact of enriching DNA methylation at the KMT2A / MLL locus. MLL amplification and rearrangements are controlled through KDM3B, G9a and DNMT1 cross-talk After establishing that DNMT1 overexpression associates with MLL gains in cancer and significantly promotes MLL alterations, we tested whether DNMT1 depletion would rescue the phenotype or whether all DNMT family members are required for MLL amplification and rearrangements. Specifically, cells were pre-depleted with at least two independent siRNAs against each DNMT family member (DNMT1, DNMT3A, and DNMT3B) before assessing whether they prevented the MLL amplification and rearrangement caused by KDM3B depletion and / or enzymatic inhibition. Only depletion of DNMT1 was able to rescue the KMT2A / MLL amplification and rearrangements caused by KDM3B inhibition in human RPE cells (Fig. 2A) and HL60 cells (Fig.2B). Additionally, genetic co-depletion of KDM3B and DNMT1 fully rescued KMT2A / MLL alterations (Fig. 2C). We further demonstrated that pre-depletion of DNMT1 prior to treatment with KDM3 inhibitor (KDM3i) also prevented the MLL alterations (Fig. 2D). Finally, we tested whether pan-DNMT inhibition (5-azacytadine, 5-AzaC),13and / or DNMT1 specific inhibition (DNMT1i) would prevent the KDM3i induced MLL alterations. Co-treatment of either 5-AzaC or DNMT1i prior to KDM3i treatment rescued MLL amplifications and rearrangements with no significant alterations to RPE cell growth (Figs. 2E, 2F, 2G). The H3K9me1 / 2 demethylase KDM3B14,15regulates H3K9me1 / 2 levels, especially at the MLL locus.16The increased H3K9me1,2 associated with reduced CTCF and MLL amplification and rearrangements. Therefore, we tested whether DNMT1 depletion was sufficient to prevent the increased H3K9me1,2 levels and the reduced CTCF occupancy at the MLL locus (i.e., exon 11). Upon co-depleting DNMT1 and KDM3B, we observed a significant rescue for H3K9me1 / 2 levels and CTCF occupancy (Figure 2H-2J). This data suggests that DNMT1, similarly to G9a, is a dominant regulator in the MLL alterations. These data further emphasize a critical role for G9a and DNMT1 in modulating the ability for MLL / KMT2A to undergo amplification and rearrangements. DNMT1 depletion or inhibition are sufficient to prevent Doxorubicin induced MLL alterations Previously, KDM3B and CTCF were shown to be downregulated by Topoisomerase II inhibitors.17Furthermore, the TopoII inhibitors like Doxorubicin (Dox) promoted MLL amplification and rearrangement through G9a and KDM3B reduced protein levels. Therefore, we hypothesized that DNMT1-G9a are likely critical for the MLL alterations observed upon Dox treatment. We tested this hypothesis by either depleting or inhibiting DNMT1 before treating cells with Dox. For all human cells tested (RPE, primary AML), we observed a complete rescue of Dox-induced MLL amplification and rearrangements (Figure 3A-3B). These data suggest that such inhibition could prevent MLL alterations in animals treated with Dox. Therefore, we pretreated mice with DNMT1i (Figure 3C-3D) or 5AzaC (Figure 3E-3F) before treating them with Dox. The cells from the spleen were isolated and scored in a double-blind format for MLL amplifications by DNA FISH. In both male and female mice, we observed a complete and significant block in Dox-induced MLL amplification when pre-treated with DNMT1i (Figure 3C-D) and 5AzaC (Figure 3E-3F). Taken together this study has identified a critical epigenetic factor in controlling CTCF occupancy and lysine methylation state at the MLL locus, while uncovering another critical approach to therapeutically targeting MLL amplification and rearrangements induced through chemotherapy. These studies provide novel biomarkers, mechanism and therapeutic avenues to understand and treat MLL altered cancers, which has further implications in controlling or understanding other cancer associated amplification and rearrangement events. TET inhibition promotes MLL alterations Next, we hypothesized that if we block DNA methylation, we could promote the MLL amplification and rearrangement phenotype. We hypothesized that blocking ten-eleven translocation (TET) methylcytosine dioxygenases, the enzymes responsible for converting 5mC to 5hmC, would promote our pathway. TET enzymes modify 5mC through oxidation generating 5hmC (Tahiliani M, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009 May 15;324(5929):930-5.). After treating RPE cells with a pan TET inhibitor (C35) (A.K. Singh, et al., Selective targeting of TET catalytic domain promotes somatic cell reprogramming, Proc. Natl. Acad. Sci. U.S.A. 117 (7) 3621-3626) for 72 hours, DNA FISH revealed that loss of TET enzymatic activity significantly increased MLL amplification and rearrangement events (Figure 4A). We then hypothesized that prior inhibition of DNA methylation, thus preventing 5mC conversion, followed by TET inhibition, which prevents an increase in 5hmC, rescues MLL amplifications and rearrangement events driven by TET inhibition. This outcome was seen where pre-inhibition of DNMT1 fully rescued the effects of TET inhibition (Figure 4B). This indicates that both 5mc and 5hmC DNA methylation levels affect the MLL phenotype. Further, selective dCas9 targeting TET1 to exon 11 of KMT2A prior to KDM3i treatment fully rescued MLL genomic alterations (Figure 4C-4D). This suggested that prior targeting of TET1 via dCas9 to the MLL locus could also prevent Dox- induced MLL genomic alterations, which was observed in (Figure 4D-4E). RNA: DNA Hybrids Stabilize the MLL Locus RNA:DNA hybrids are secondary structures that are generated during DNA replication, transcription, and repair.1These structures have several important physiological roles including chromatin structure integrity and regulation of gene expression.34Studies have established that DNA methylation levels impact the stability of these structures.35-37Public DRIP-seq data shows that RNA:DNA hybrids are located adjacent to the MLL BCR,38and therefore we hypothesized that the presence of these hybrids stabilize the region. To assess whether loss of RNA:DNA hybrids impact MLL amplifications and rearrangements, we overexpressed wild-type (WT) or catalytic dead (D210N) RNaseH1, an enzyme that selectively degrades hybrids.39We observed a significant increase in MLL amplification and rearrangements when WT but not D210N, RNaseH1 was overexpressed (Figure 5A). We then hypothesized that DNMT1 depletion could block RNaseH overexpression-induced MLL alterations. Using siRNA, we determined that depletion of DNMT1 prior to overexpression of RNaseH rescues RNaseH overexpression- induced MLL alterations (Figure 5B). To determine whether the RNA:DNA hybrid within MLL was critical, we used an RNaseH-dCas9 system targeted to the MLL BCR. We found that only WT RNaseH1 targeted to the MLL BCR was sufficient to promote MLL amplification and rearrangement events (Figure 5C). Further, we hypothesized that RNaseH1 overexpression could influence CTCF binding at MLL due to its impact on MLL genomic alterations. Using Chromatin immunoprecipitation (ChIP) qPCR, we overexpressed wild type (WT) or catalytic dead (D210N) RNaseH1 in RPE cells and performed ChIP using a CTCF antibody to quantify signal of CTCF at exon 11 of the KMT2A / MLL locus. We saw a modest decrease of CTCF occupancy at MLL for the WT treated cells compared to control (GFP) (Figure 5D). The data presented herein provide new treatment approaches targeting cancer. For example, topoisomerase toxicity can be abrogated by inhibiting DNMT1 inhibition alone, before or during treatment with agents which induce breakpoints and amplifications (e.g., doxorubicin). To further reduce MLL / KMT2a amplifications and rearrangements, DNMT1 inhibitors can be combined with at least one G9a related inhibitor. In another approach, increased KMT2A / MLL in patients having alterations in KDM3B or 5q loss cancers (e.g., AML, MDS) can be treated with a similar regimen, e.g., DNMT1 inhibitor, alone or in combination a G9a inhibitor. The information disclosed herein can also be used to suppress KMT2A / MLL through dCas9 or related targeting of KDM3B in cells thereby reducing KMT2A / MLL alterations in MLL rearranged and following treatment with topoII, providing a preventative or suppressive method for their appearance and associated disease. 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Claims

WHAT IS CLAIMED IS:

1. A method for reducing chemotherapy- induced DNA amplification and breakpoint formation in a patient in need thereof, the method comprising administration of an effective amount of an DNMT1 inhibitor in a pharmaceutically acceptable carrier, wherein said inhibitor is administered prior to or during said chemotherapy, thereby inhibiting chemotherapy induced DNA amplification and breakpoint formation.

2. The method of claim 1 further comprising administration of at least one additional agent which i) increases KDM3B expression or function; ii) inhibits G9a expression or function; and iii) inhibits H3K9 methyltransferase expression or function.

3. The method of claim 2, wherein said G9a inhibitor is selected from an siRNA GCUCUAACUGAACAACUAAtt (SEQ ID NO: 13); or CGCUGAUUUUCGAGUGUAAtt (SEQ ID NO: 14) 4. The method of claim 2, wherein said KDM3B agonist and G9a inhibitor are administered.

5. The method of any one of claims 1 to 4, wherein the chemotherapeutic agent is a topoisomerase II inhibitor.

6. The method one of claims 1 to 4, wherein the topoisomerase II inhibitor is doxorubicin, daunorubicin, etoposide or Topoisomerase II alpha or beta.

7. The method of any one of the preceding claims, wherein said DNMT1 inhibitor is an inhibitory nucleic acid selected from an siRNA, an antisense oligonucleotide, an shRNA, and a ribozyme having sufficient sequence homology to said DNMT1 encoding nucleic acid to reduce expression thereof in a target cell.

8. The method of claim 7, wherein said inhibitory nucleic acid comprises one or more modified nucleotides or nucleosides.

9. The method of claim 6, wherein said inhibitor nucleic acid is present in an expression vector and, or operably linked to a lipid nanoparticle.

10. The method of any one of claims 1 to 6, wherein said DNMT1 inhibitor is a small molecule selected from decitabine, azacytidine and GSK3685032.

11. The method of any one of the preceding claims wherein expression levels of DNMT1 in said patient are determined prior to treatment.

12. The method of any one of the preceding claims wherein said 5q / KDM3B LOH status in said patient is determined prior to treatment.

13. The method of any one of the preceding claims wherein said rearrangements are present in a cancer patient, said cancer being selected from acute myeloid leukemia, mixed lineage leukemia, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, colorectal cancer, gastic cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, liver metastases, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, thyroid carcinoma, anaplastic thyroid cancer, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, glioblastoma, and retinoblastoma.

14. The method of any one of the preceding claims further comprising administration of at least one anti-cancer agent selected from a BCL2 inhibitor, an alkylating agent, anti-metabolic antineoplastic agent, anti-tumor antibiotic, anti-tumor botanical, platinum compound antineoplastic agent, hormonal balance antineoplastic agent, rituximab, bevacizumab, trastuzumab, imatinib, dinoxetine, cetuximab, nilotinib, sorafenib, PD-1 inhibitor, PD-L1 inhibitor, a CTLA4 inhibitor, cyclophosphamide, ifosfamide and thiotepa, methotrexate, mercaptopurine, fluorouracil and cytarabine, bleomycin, daunorubicin, actinomycin D, mitomycin, doxorubicin and mitoxantrone, vincristine, etoposide, teniposide, paclitaxel, docetaxel, cisplatin, carboplatin, oxaliplatin, leuprolide, tamoxifen, flutamide, formestane, and arsenic trioxide, crizotinib, bosutinib, gilteritinib, amuvatinib, Sunitinib, cabozantinib, foretinib, rebastinib, celastrol and dihydroartemisinin.

15. The method of any one of claims 2 to 14, wherein said agents act synergistically to kill cancer cells.

16. A method for treating cancer in a 5q / KDM3B LOH patient in need thereof, comprising a) administration of an effective amount of at least one agent that inactivates KDM3B in cells and an DMT1 agonist, thereby increasing KMT2A / MLL alterations and rearrangements, and b) contacting the cells of step a) with a topoII inhibitor, said combination acting synergistically to cause cancer cell death.

17. The method of claim 16, wherein KDM3B is inactivating by genetic dCA9 mediated genetic alteration and results in increased apoptosis in targeted cells.

18. The method of claim 16, wherein drug sensitivity is increased in said patient 19. The method of claim 16, further comprising administration of a G9a agonist.

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