Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Leukemia stem cells (LSCs) drive the initiation and perpetuation of AML, are quantifiably associated with worse clinical outcomes, and often persist after conventional chemotherapy resulting in relapse1,2,3,4,5. In this report, we show that treatment of older patients with AML with the B cell lymphoma 2 (BCL-2) inhibitor venetoclax in combination with azacitidine results in deep and durable remissions and is superior to conventional treatments. We hypothesized that these promising clinical results were due to targeting LSCs. Analysis of LSCs from patients undergoing treatment with venetoclax + azacitidine showed disruption of the tricarboxylic acid (TCA) cycle manifested by decreased α-ketoglutarate and increased succinate levels, suggesting inhibition of electron transport chain complex II. In vitro modeling confirmed inhibition of complex II via reduced glutathionylation of succinate dehydrogenase. These metabolic perturbations suppress oxidative phosphorylation (OXPHOS), which efficiently and selectively targets LSCs. Our findings show for the first time that a therapeutic intervention can eradicate LSCs in patients with AML by disrupting the metabolic machinery driving energy metabolism, resulting in promising clinical activity in a patient population with historically poor outcomes.
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Patient-related clinical data not included in the paper were generated as part of a multicenter clinical trial (NCT02203773). A detailed description of the dose escalation portion of the study has been published (Dinardo et al.)1. The dose expansion portion of the study is now complete and the manuscript describing these data is currently in preparation. All DNA and RNA raw and analyzed sequencing data can be found at the GEO database and are available via accession number GSE116481 (single-cell RNA-seq) and accession number GSE116567 (bulk RNA-seq).
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In memory of Richard Berger, a warrior in all aspects of life, who bravely confronted every obstacle and brought courage and inspiration to us, his family and all who were privileged enough to know him. Grant support: D.A.P is supported by the University of Colorado Department of Medicine Outstanding Early Career Scholar Program. B.M.S. and C.T.J are supported by a pilot grant provided by the University of Colorado RNA Bioscience Initiative. C.L.J. was supported by the American Cancer Society (25A5072) and the Colorado Clinical and Translational Sciences Institute (AEF CCTSI YR9 CO 2301425). A.D. is supported by the Webb-Waring Early Career award 2017 sponsored by the Boettcher Foundation. C.T.J. is generously supported by the Nancy Carroll Allen Chair in Hematology Research and NIH (grant R01CA200707). We thank J. DeGregori and E. Pietras for their comments on our manuscript.