Targeting MCL1-driven anti-apoptotic pathways to overcome hypomethylating agent resistance inRAS-mutated chronic myelomonocytic leukemia

Abstract

ABSTRACTRASpathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Using single-cell, multi-omics technologies, we sought to dissect the biological mechanisms underlying the initiation and progression ofRASpathway–mutated CMML. We found thatRASpathway mutations induced the transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs), which underwent proliferation and monocytic differentiation in response to cell-intrinsic and -extrinsic inflammatory signaling that also impaired immune cells’ functions. HSPCs expanded at disease progression and relied on the NF-KB pathway effector MCL1 to maintain their survival, which explains why patients withRASpathway– mutated CMML do not benefit from BCL2 inhibitors such as venetoclax. Our study has implications for developing therapies to improve the survival of patients withRASpathway– mutated CMML.