Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance
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- dc.contributor.author Takao, Sumiko
- dc.contributor.author Morell, Victor
- dc.contributor.author Uni, Masahiro
- dc.contributor.author Slavit, Alicia
- dc.contributor.author Rha, Sophia
- dc.contributor.author Cheng, Shuyuan
- dc.contributor.author Schmalbrock, Laura K.
- dc.contributor.author Brown, Fiona C.
- dc.contributor.author Beneyto Calabuig, Sergi
- dc.contributor.author Koche, Richard P.
- dc.contributor.author Velten, Lars
- dc.contributor.author Kentsis, Alex
- dc.date.accessioned 2025-09-04T06:39:07Z
- dc.date.available 2025-09-04T06:39:07Z
- dc.date.issued 2025
- dc.description.abstract Cancer stem cells are essential for initiation and therapy resistance of many cancers, including acute myeloid leukemias (AML). Here, we apply functional genomic profiling to diverse human leukemias, including high-risk MLL- and NUP98-rearranged specimens, using label tracing in vivo. Human leukemia propagation is mediated by a rare quiescent label-retaining cell (LRC) population undetectable by current immunophenotypic markers. AML quiescence is reversible, preserving genetic clonal competition and epigenetic inheritance. LRC quiescence is defined by distinct promoter-centered chromatin and gene expression dynamics controlled by an AP-1/ETS transcription factor network, where JUN is necessary and sufficient for LRC quiescence and associated with persistence and chemotherapy resistance in diverse patients. This enables prospective isolation and manipulation of immunophenotypically-varied leukemia stem cells, establishing the functions of epigenetic plasticity in leukemia development and therapy resistance. These findings offer insights into leukemia stem cell quiescence and the design of therapeutic strategies for their clinical identification and control.
- dc.format.mimetype application/pdf
- dc.identifier.citation Takao S, Morell V, Uni M, Slavit A, Rha S, Cheng S, et al. Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance. Nat Commun. 2025 Apr 3;16(1):3196. DOI: 10.1038/s41467-025-58370-9
- dc.identifier.doi http://dx.doi.org/10.1038/s41467-025-58370-9
- dc.identifier.issn 2041-1723
- dc.identifier.uri http://hdl.handle.net/10230/71103
- dc.language.iso eng
- dc.publisher Nature Research
- dc.relation.ispartof Nat Commun. 2025 Apr 3;16(1):3196
- dc.rights © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, 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 you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. 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-nc-nd/4.0/.
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
- dc.subject.keyword Acute myeloid leukaemia
- dc.subject.keyword Cancer stem cells
- dc.subject.keyword Paediatric cancer
- dc.title Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion