Targeting MCL1-driven anti-apoptotic pathways overcomes blast progression after hypomethylating agent failure in chronic myelomonocytic leukemia
Guillermo Montalban‐Bravo, Natthakan Thongon, Juan José Rodríguez‐Sevilla, Feiyang Ma, Irene Gañán‐Gómez, Hui Yang, Yi June Kim, Vera Ademà, Bethany Wildeman, Tomoyuki Tanaka, Faezeh Darbaniyan, Gheath Alatrash, Karen C. Dwyer, Sanam Loghavi, Rashmi Kanagal‐Shamanna, Xingzhi Song, Jianhua Zhang, Koichi Takahashi, Hagop M. Kantarjian, Guillermo Garcia‐Manero, Simona Colla
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. Here, using single-cell, multi-omics technologies, we seek to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We identify that RAS pathway mutations induce transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs) and downstream monocytic populations in response to cell-intrinsic and -extrinsic inflammatory signaling that also impair the functions of immune cells. HSPCs expand at disease progression after therapy with HMA or the BCL2 inhibitor venetoclax and rely on the NF-κB pathway effector MCL1 to maintain survival. Our study has implications for the development of therapies to improve the survival of patients with RAS pathway-mutated CMML.