Rodríguez-Sevilla, Juan JoséGañán-Gómez, IreneMa, FeiyangChien, KellyRey, Mónica delLoghavi, SanamMontalban-Bravo, GuillermoAdemá, VeraWildeman, BethanyKanagal-Shamanna, RashmiBazinet, AlexandreChifotides, Helen T.Thongon, NatthakanCalvo Gonzalo, XavierHernández-Rivas, Jesús MaríaDíez-Campelo, MaríaGarcia-Manero, GuillermoColla, Simona2025-07-072025-07-072024Rodriguez-Sevilla JJ, Ganan-Gomez I, Ma F, Chien K, Del Rey M, Loghavi S, et al. Hematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes. Nat Commun. 2024 Mar 18;15(1):2428. DOI: 10.1038/s41467-024-46424-32041-1723http://hdl.handle.net/10230/70850The molecular mechanisms of venetoclax-based therapy failure in patients with acute myeloid leukemia were recently clarified, but the mechanisms by which patients with myelodysplastic syndromes (MDS) acquire secondary resistance to venetoclax after an initial response remain to be elucidated. Here, we show an expansion of MDS hematopoietic stem cells (HSCs) with a granulo-monocytic-biased transcriptional differentiation state in MDS patients who initially responded to venetoclax but eventually relapsed. While MDS HSCs in an undifferentiated cellular state are sensitive to venetoclax treatment, differentiation towards a granulo-monocytic-biased transcriptional state, through the acquisition or expansion of clones with STAG2 or RUNX1 mutations, affects HSCs' survival dependence from BCL2-mediated anti-apoptotic pathways to TNFα-induced pro-survival NF-κB signaling and drives resistance to venetoclax-mediated cytotoxicity. Our findings reveal how hematopoietic stem and progenitor cell (HSPC) can eventually overcome therapy-induced depletion and underscore the importance of using close molecular monitoring to prevent HSPC hierarchical change in MDS patients enrolled in clinical trials of venetoclax.application/pdfeng© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-024-46424-3CancerMyelodysplastic syndromeOncologyinfo:eu-repo/semantics/openAccess