Journal
CANCER RESEARCH
Volume 82, Issue 23, Pages 4325-4339Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-22-1293
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Funding
- Cancer Research Society (SMC)
- Princess Margaret Cancer Foundation (SMC)
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STAT5 was identified as a critical mediator of resistance to IDH inhibitors, suggesting that combining STAT5 and IDH inhibitors may be an effective treatment strategy for IDH-mutated AML.
Mutant isocitrate dehydrogenase 1 (IDH1) and IDH2 block the differentiation of acute myeloid leukemia (AML) cells through production of R-2-hydroxyglutarate (R-2-HG). IDH inhibitors can induce differentiation of AML cells by lowering R-2-HG but have limited clinical efficacy as single agents. Here, we performed a genome-wide CRISPR knockout screen in an Idh1-mutated hematopoietic progenitor cell line to identify genes that increased the differentiation response to ivosidenib, an IDH1 inhibitor. The screen identified C-type lectin member 5a (Clec5a), which encodes a spleen tyrosine kinase (SYK)-coupled surface receptor, as one of the top hits. Knockout of Clec5a and Syk rendered cells more sensitive to ivosidenib-induced differ-entiation through a reduction in STAT5-dependent expression of stemness-related genes, including genes in the homeobox (HOX) family. Importantly, direct inhibition of STAT5 activity was sufficient to increase the differentiation response to IDH inhi-bitors in primary human IDH1- and IDH2-mutated AML cells, including those harboring mutations in receptor tyrosine kinase (RTK) and MAPK genes that have been linked to drug resistance. In patient-derived xenograft models of IDH1-mutated AML, combination treatment with ivosidenib and the STAT5 inhibitor pimozide was superior to each agent alone in inducing differ-entiation in leukemic cells without compromising normal hema-topoiesis. These findings demonstrate that STAT5 is a critical mediator of resistance to IDH inhibitors and provide the ration-ale for combining STAT5 and IDH inhibitors in the treatment of IDH-mutated AML.
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