Data from <i>IDH1</i>-Mutant Preleukemic Hematopoietic Stem Cells Can Be Eliminated by Inhibition of Oxidative Phosphorylation

Abstract

<div>Abstract<p>Rare preleukemic hematopoietic stem cells (pHSC) harboring only the initiating mutations can be detected at the time of acute myeloid leukemia (AML) diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene editing to model <i>isocitrate dehydrogenase 1</i> (<i>IDH1</i>) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSC). We confirm that <i>IDH1</i>-driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, <i>IDH1</i>-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in the complete eradication of <i>IDH1</i>-mutant pHSCs but not <i>IDH2</i>-mutant pHSCs or wild-type HSCs. Our results indicate that <i>IDH1</i>-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent the development and relapse of leukemia.</p>Significance:<p>A high burden of pHSCs is associated with worse overall survival in AML. Using single-cell sequencing, metabolic assessment, and gene-edited human models, we find human pHSCs with <i>IDH1</i> mutations to be metabolically vulnerable and sensitive to eradication by complex I inhibition.</p><p><i><a href="https://aacrjournals.org/bloodcancerdiscov/article/doi/10.1158/2643-3230.BCD-23-0255" target="_blank">See related commentary by Steensma, p. 83.</a></i></p><p><i><a href="https://aacrjournals.org/bloodcancerdiscov/article/doi/10.1158/2643-3230.BCD-5-2-ITI" target="_blank">This article is featured in Selected Articles from This Issue, p. 80</a></i></p></div>