IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by oxphos inhibition

Rare preleukemic hematopoietic stem cells (pHSCs) harboring only the initiating mutations can be detected at the time of AML diagnosis. pHSCs are likely the origin of leukemia and a potential reservoir for relapse but remain challenging to eradicate. Using primary human samples and gene-editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show biological, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSCs). We confirm that IDH1 mutations are present in patients with clonal cytopenia of undetermined significance, but not in individuals with clonal hematopoiesis of indeterminate potential, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation with a block in differentiation, downregulation of MHC Class II genes and reprogramming of oxphos metabolism. Critically, IDH1-mutant pHSCs showed reduced metabolic activity distinct from normal HSCs and inhibition of oxphos resulted in complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wildtype HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors to prevent development and relapse of leukemia. Overall design: Human cord blood derived HSPCs from four donors were genetically engineered to expressed wildtype or mutant IDH1 or IDH2 and an AAVS1 GFP only control and subjected to RNA sequencing.