GSE201661
Inhibition of mutant IDH1 promotes cycling of acute myeloid leukemia stem cells [RNAseq_AG120_AZA_treatment]
Acute myeloid leukemia (AML) tumors are comprised of multiple cell types with distinct capabilities to propagate the disease and resist therapy. Approximately 20% of AML patients carry gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 or -2 that result in over-production of the onco-metabolite D-2-hydroxyglutarate (2-HG). Small molecule inhibitors that block 2-HG synthesis can induce complete morphological remission even in heavily pre-treated AML patients. However, almost all patients eventually relapse with analysis of clinical samples suggesting that a population of IDH mutant cells is able to persist during treatment eventually acquiring 2-HG independence and drug resistance. Herein we characterized the molecular and cellular responses to the clinical IDH1 inhibitor AG-120 (Ivosidenib) at high resolution using a novel multi-allelic mouse model of IDH1 mutant AML. We demonstrate that inhibition of mutant IDH1 exerts cell type-dependent effects on leukemic cells promoting delayed disease regression. Although single agent AG-120 treatment was not able to fully eradicate the disease, we uncovered that it increases cycling of rare leukemic stem cells (LSCs) and triggers transcriptional upregulation of the pyrimidine salvage pathway. Accordingly, AG-120 sensitized IDH1 mutant AML to the cytosine analogue hypomethylating agent azacitidine with the combination of AG-120 and azacitidine showing vastly improved efficacy in vivo. Our data highlight the impact of non-genetic heterogeneity on treatment response and provide mechanistic rationale for a drug combination that is being tested in clinical trials. Overall design: We investigated the consequences of the combined AG-120 and azacitidine treatment on DNA methylation and gene expression using reduced representation bisulfite sequencing (RRBS) and RNAseq