Targeting MCL1-driven anti-apoptotic pathways to overcome hypomethylating agent resistance in RAS-mutated chronic myelomonocytic leukemia
Montalban-Bravo, G.; Ma, F.; Thongon, N.; Yang, H.; Ganan-Gomez, I.; Rodriguez-Sevilla, J. J.; Adema, V.; Wildeman, B.; Lockyer, P. P.; Kim, Y. J.; Tanaka, T.; Darbaniyan, F.; Pancholy, S.; Zhang, G.; Al-Atrash, G.; Dwyer, K.; Takahashi, K.; Garcia-Manero, G.; Kantarjian, H.; Colla, S.
Show abstract
RAS pathway 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 of RAS pathway-mutated CMML. We found that RAS pathway 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 with RAS pathway- mutated CMML do not benefit from BCL2 inhibitors such as venetoclax. Our study has implications for developing therapies to improve the survival of patients with RAS pathway- mutated CMML.
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