{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:42:15Z","timestamp":1787002935122,"version":"build-2736575974"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T00:00:00Z","timestamp":1710720000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T00:00:00Z","timestamp":1710720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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\n                    <jats:italic>STAG2<\/jats:italic>\n                    or\n                    <jats:italic>RUNX1<\/jats:italic>\n                    mutations, affects HSCs\u2019 survival dependence from BCL2-mediated anti-apoptotic pathways to TNF\u03b1-induced pro-survival NF-\u03baB 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.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-46424-3","type":"journal-article","created":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T11:02:31Z","timestamp":1710759751000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Hematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes"],"prefix":"10.1038","volume":"15","author":[{"given":"Juan Jose","family":"Rodriguez-Sevilla","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Ganan-Gomez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6260-0787","authenticated-orcid":false,"given":"Feiyang","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6024-1613","authenticated-orcid":false,"given":"Kelly","family":"Chien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Del Rey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8980-3202","authenticated-orcid":false,"given":"Sanam","family":"Loghavi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4533-5176","authenticated-orcid":false,"given":"Guillermo","family":"Montalban-Bravo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6051-4378","authenticated-orcid":false,"given":"Vera","family":"Adema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany","family":"Wildeman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7829-5249","authenticated-orcid":false,"given":"Rashmi","family":"Kanagal-Shamanna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Bazinet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen T.","family":"Chifotides","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natthakan","family":"Thongon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Calvo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas Mar\u00eda","family":"Hern\u00e1ndez-Rivas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1467-6779","authenticated-orcid":false,"given":"Maria","family":"D\u00edez-Campelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3631-2482","authenticated-orcid":false,"given":"Guillermo","family":"Garcia-Manero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6583-8910","authenticated-orcid":false,"given":"Simona","family":"Colla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,18]]},"reference":[{"key":"46424_CR1","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/s41591-022-01696-4","volume":"28","author":"I Ganan-Gomez","year":"2022","unstructured":"Ganan-Gomez, I. et al. Stem cell architecture drives myelodysplastic syndrome progression and predicts response to venetoclax-based therapy. Nat. Med. 28, 557\u2013567 (2022).","journal-title":"Nat. Med."},{"key":"46424_CR2","doi-asserted-by":"publisher","first-page":"e756","DOI":"10.1016\/S2352-3026(22)00216-2","volume":"9","author":"A Bazinet","year":"2022","unstructured":"Bazinet, A. et al. Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1-2 study. Lancet Haematol. 9, e756\u2013e765 (2022).","journal-title":"Lancet Haematol."},{"key":"46424_CR3","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1158\/2159-8290.CD-19-0125","volume":"9","author":"T Nechiporuk","year":"2019","unstructured":"Nechiporuk, T. et al. The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells. Cancer Discov. 9, 910\u2013925 (2019).","journal-title":"Cancer Discov."},{"key":"46424_CR4","doi-asserted-by":"publisher","first-page":"3830","DOI":"10.1002\/cncr.25247","volume":"116","author":"E Jabbour","year":"2010","unstructured":"Jabbour, E. et al. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer 116, 3830\u20133834 (2010).","journal-title":"Cancer"},{"key":"46424_CR5","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1158\/2159-8290.CD-19-0710","volume":"10","author":"S Pei","year":"2020","unstructured":"Pei, S. et al. Monocytic subclones confer resistance to venetoclax-based therapy in patients with acute myeloid leukemia. Cancer Discov. 10, 536\u2013551 (2020).","journal-title":"Cancer Discov."},{"key":"46424_CR6","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1016\/j.stem.2020.07.021","volume":"27","author":"CL Jones","year":"2020","unstructured":"Jones, C. L. et al. Nicotinamide metabolism mediates resistance to venetoclax in relapsed acute myeloid leukemia stem cells. Cell Stem Cell 27, 748\u2013764.e744 (2020).","journal-title":"Cell Stem Cell"},{"key":"46424_CR7","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1038\/s43018-020-00126-z","volume":"1","author":"BM Stevens","year":"2020","unstructured":"Stevens, B. M. et al. Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells. Nat. Cancer 1, 1176\u20131187 (2020).","journal-title":"Nat. Cancer"},{"key":"46424_CR8","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.100940","volume":"4","author":"JJ Rodriguez-Sevilla","year":"2023","unstructured":"Rodriguez-Sevilla, J. J., Adema, V., Garcia-Manero, G. & Colla, S. Emerging treatments for myelodysplastic syndromes: Biological rationales and clinical translation. Cell Rep. Med. 4, 100940 (2023).","journal-title":"Cell Rep. 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HemaSphere 7, https:\/\/doi.org\/10.1097\/01.HS9.0000967600.18588.ff (2023).","DOI":"10.1097\/01.HS9.0000967600.18588.ff"},{"key":"46424_CR11","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1586\/14737159.2016.1142374","volume":"16","author":"R Kanagal-Shamanna","year":"2016","unstructured":"Kanagal-Shamanna, R. et al. Principles of analytical validation of next-generation sequencing based mutational analysis for hematologic neoplasms in a CLIA-certified laboratory. Expert Rev. Mol. Diagn. 16, 461\u2013472 (2016).","journal-title":"Expert Rev. Mol. Diagn."},{"key":"46424_CR12","doi-asserted-by":"publisher","first-page":"2454","DOI":"10.1182\/blood-2012-03-420489","volume":"120","author":"PL Greenberg","year":"2012","unstructured":"Greenberg, P. L. et al. Revised international prognostic scoring system for myelodysplastic syndromes. 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Single-cell analysis reveals the continuum of human lympho-myeloid progenitor cells. Nat. Immunol. 19, 85\u201397 (2018).","journal-title":"Nat. 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All other authors report no competing interests relative to this work.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2428"}}