RAS-mutant leukaemia stem cells drive clinical resistance to venetoclax

• 成果类型: Article
• 署名作者: Sango, Junya; Carcamo, Saul; Sirenko, Maria; Maiti, Abhishek; Mansour, Hager; Ulukaya, Gulay; Tomalin, Lewis E.; Cruz-Rodriguez, Nataly; Wang, Tiansu; Olszewska, Malgorzata; Olivier, Emmanuel; Jaud, Manon; Nadorp, Bettina; Kroger, Benjamin; Hu, Feng; Silverman, Lewis; Chung, Stephen S.; Wagenblast, Elvin; Chaligne, Ronan; Eisfeld, Ann-Kathrin; Demircioglu, Deniz; Landau, Dan A.; Lito, Piro; Papaemmanuil, Elli; Dinardo, Courtney D.; Hasson, Dan; Konopleva, Marina; Papapetrou, Eirini P.
• 署名单位: Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; University of Texas System; UTMD Anderson Cancer Center; New York University; New York University; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Memorial Sloan Kettering Cancer Center; University of Texas System; University of Texas Southwestern Medical Center; Cornell University; Weill Cornell Medicine; University System of Ohio; Ohio State University; James Cancer Hospital & Solove Research Institute; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5422
• DOI: 10.1038/s41586-024-08137-x
• 发表日期: 2024-12-05
• 关键词: acute myeloid-leukemia; clonal evolution; CLASSIFICATION; mutations; aml; expression; diagnosis; disease; abt-199; target

摘要

Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukaemia, upon progression or relapsed/refractory disease1, 2, 3, 4, 5-6. Here, by using human leukaemogenesis models, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte-monocyte progenitors) harbouring previously acquired driver mutations, showing that advanced leukaemic clones can originate from a different cell type in the haematopoietic hierarchy than ancestral clones. Furthermore, we demonstrate that RAS-mutant leukaemia stem cells (LSCs) give rise to monocytic disease, as observed frequently in patients with poor responses to treatment with the BCL2 inhibitor venetoclax. We show that this is because RAS-mutant LSCs, in contrast to RAS-wild-type LSCs, have altered BCL2 family gene expression and are resistant to venetoclax, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver shapes the non-genetic cellular hierarchy of acute myeloid leukaemia by imposing a specific LSC target cell restriction and critically affects therapeutic outcomes in patients.