Hematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes
Mostra el registre complet Registre parcial de l'ítem
- dc.contributor.author Rodríguez-Sevilla, Juan José
- dc.contributor.author Gañán-Gómez, Irene
- dc.contributor.author Ma, Feiyang
- dc.contributor.author Chien, Kelly
- dc.contributor.author Rey, Mónica del
- dc.contributor.author Loghavi, Sanam
- dc.contributor.author Montalban-Bravo, Guillermo
- dc.contributor.author Ademá, Vera
- dc.contributor.author Wildeman, Bethany
- dc.contributor.author Kanagal-Shamanna, Rashmi
- dc.contributor.author Bazinet, Alexandre
- dc.contributor.author Chifotides, Helen T.
- dc.contributor.author Thongon, Natthakan
- dc.contributor.author Calvo Gonzalo, Xavier
- dc.contributor.author Hernández-Rivas, Jesús María
- dc.contributor.author Díez-Campelo, María
- dc.contributor.author Garcia-Manero, Guillermo
- dc.contributor.author Colla, Simona
- dc.date.accessioned 2025-07-07T06:34:43Z
- dc.date.available 2025-07-07T06:34:43Z
- dc.date.issued 2024
- dc.description.abstract The 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.
- dc.format.mimetype application/pdf
- dc.identifier.citation Rodriguez-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/s41467-024-46424-3
- dc.identifier.doi http://dx.doi.org/10.1038/s41467-024-46424-3
- dc.identifier.issn 2041-1723
- dc.identifier.uri http://hdl.handle.net/10230/70850
- dc.language.iso eng
- dc.publisher Nature Research
- dc.relation.ispartof Nat Commun. 2024 Mar 18;15(1):2428
- dc.rights © 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/.
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/
- dc.subject.keyword Cancer
- dc.subject.keyword Myelodysplastic syndrome
- dc.subject.keyword Oncology
- dc.title Hematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion