{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:39:38Z","timestamp":1768505978343,"version":"3.49.0"},"posted":{"date-parts":[[2023,4,8]]},"group-title":"Cancer Biology","reference-count":48,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,4,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  <jats:italic>RAS<\/jats:italic>\n                  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\n                  <jats:italic>RAS<\/jats:italic>\n                  pathway\u2013mutated CMML. We found that\n                  <jats:italic>RAS<\/jats:italic>\n                  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\u2019 functions. HSPCs expanded at disease progression and relied on the NF-\n                  <jats:sub>K<\/jats:sub>\n                  B pathway effector MCL1 to maintain their survival, which explains why patients with\n                  <jats:italic>RAS<\/jats:italic>\n                  pathway\u2013 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\n                  <jats:italic>RAS<\/jats:italic>\n                  pathway\u2013 mutated CMML.\n                <\/jats:p>","DOI":"10.1101\/2023.04.07.535928","type":"posted-content","created":{"date-parts":[[2023,4,9]],"date-time":"2023-04-09T00:10:12Z","timestamp":1680999012000},"source":"Crossref","is-referenced-by-count":0,"title":["Targeting MCL1-driven anti-apoptotic pathways to overcome hypomethylating agent resistance in\n                  <i>RAS<\/i>\n                  -mutated chronic myelomonocytic leukemia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4533-5176","authenticated-orcid":false,"given":"Guillermo","family":"Montalban-Bravo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feiyang","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6169-403X","authenticated-orcid":false,"given":"Natthakan","family":"Thongon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene Ganan-","family":"Gomez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juanjo 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