iPSC-derived leukemia stem cell model for CML drug resistance screening
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Solution Overview
Problem
Current treatments for chronic myeloid leukemia (CML) face challenges in effectively targeting leukemia stem cells due to their rarity and the development of therapeutic resistance, limiting the efficacy of existing drugs.
Innovation Solution
The development of a kit and pharmaceutical composition that includes a combination of a tyrosine kinase inhibitor, such as imatinib, and an inhibitor of specific gene targets like OLFM4, using siRNA or antibodies to target BCR-ABL and other resistance-related genes, to enhance the treatment of CML by modulating drug resistance and identifying candidate therapeutic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If tyrosine kinase inhibitors are used to treat CML, then leukemia cell proliferation is inhibited, but therapeutic resistance develops limiting long-term efficacy
Solution Approach 1:
The patent combines tyrosine kinase inhibitors with inhibitors targeting multiple resistance-related genes (OLFM4, HLA-DRB, GPNMB, OLR1, HLA-DRA, ACP5, C3, TLR8, APOE, FPR3, RBP7, CYP27A1, TPSB2, PLEKHG5, ABCG1, MS4A7, SULF2, SLC11A1, CCL13, LGALS3, LRP1, GRN, SLAMF8, HLA-DMB, COLEC12, ALOX5AP, IL4I1, CEACAM8, C19orf59, IFI30, FCGR2c, SLCO2B1, C1QB, CCL20, CXCL16, CHI3L1, FBP1, ALDH2, SLC15A3, LILRB5, TM6SF1, RETN, CLEC4A, BCL2A1, ARHGEF10L, NDFIP2, CAPG, SLC8A1, C1QA, HLA-DPA1, STAG, DPYD, HLA-DMA, LGMN, SEMA6B, TNFSF12, MAL, COL8A2, ITGAX, IL9R, MATN2, SLC7A7, KYNU, APOC1, BTG2, C3AR1, CTSS, ALOX15, HLA-B, GIMAP8, TUBA1A, DNASE2, CD2, SBF2, CD68, BMF, S100A10, TBC1D2, SLC37A2, BHLHE40, RTN1, CEACAM1, FLVCR2, CCDC92, FCGR2B, MILR1, LY86, FOLR2, CLEC12A, PLD2, AHNAK, CEACAM4, CD300LF, CTSH, NCF1, S100A6, ADAMDEC1, PILRA, SMAD7, PMP22, TYROBP, NPC2, NLRC4, LGALS1, RNF19B, OSCAR, ALOX5, CST3, DENND2D, NPL, ASAH1, LAPTM5, MYO7B, TRIM22, PPARG, GIMAP1-GIMAP5, RENBP, PREX1, CD52, C4orf34, SAMHD1, HK3, QPCT, GADD45G, CEACAM21, TBX3, SORL1, INSIG1, SIGLEC6, CD38, TP531NP1, NCOA3, FILIP1L, NAPSA, SKIL, and TCN1) to overcome drug resistance while maintaining the anti-proliferative effect of the tyrosine kinase inhibitor
Solution Approach 2:
The patent segments the resistance mechanism into multiple independent gene targets, allowing selective inhibition of specific resistance pathways while preserving the primary anti-leukemia activity of the tyrosine kinase inhibitor
2Reliability
If leukemia stem cells are targeted to achieve definitive cure, then long-term remission is possible, but rarity of LSCS limits study and treatment development
Solution Approach 1:
The patent uses induced pluripotent stem cells (iPSCs) derived from CML patient cells as a copy or surrogate model for the rare leukemia stem cells, enabling comprehensive study and drug screening without requiring direct access to the scarce LSCS population
Solution Approach 2:
The patent performs preliminary characterization of resistance gene expression patterns in iPSC-derived leukemia stem cell-like cells before clinical treatment, allowing identification of appropriate inhibitor combinations in advance of patient treatment
Data Source
AI summary
Disclosed herein are compositions and methods to treat and reduce therapeutic resistance in chronic myelogenous leukemia. Also disclosed herein are methods to generate leukemia stem cell like cells (iLSCs) generated from CML patient-derived iPSCs, and methods for utilizing iLSCs in screens to identify modulators of CML drug resistance and gene targets that underlie CML drug resistance.