Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance
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.
Authors
- Sumiko Takao (ORCID: https://orcid.org/0000-0001-5573-1677)
- Laura K. Schmalbrock (ORCID: https://orcid.org/0000-0002-6080-6175)
- Fiona C. Brown (ORCID: https://orcid.org/0000-0001-9711-9769)
- Victor Morell (ORCID: https://orcid.org/0000-0002-7071-1030)
- Alex Kentsis (ORCID: https://orcid.org/0000-0002-8063-9191)
- Lars Velten (ORCID: https://orcid.org/0000-0002-1233-5874)
- Richard P. Koche (ORCID: https://orcid.org/0000-0002-6820-5083)
- Sergi Beneyto‐Calabuig (ORCID: https://orcid.org/0000-0003-3773-8239)
- Shuyuan Cheng (ORCID: https://orcid.org/0000-0003-0746-509X)
- Alicia Slavit
- Masahiro Uni (ORCID: https://orcid.org/0009-0005-8418-0743)
- Sophia Rha
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Universitat Pompeu Fabra (ES)
- Cornell University (US)
- Kettering University (US)
- Centre for Genomic Regulation (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-03
- DOI
- https://doi.org/10.1038/s41467-025-58370-9
- Citations
- 13
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 10.48
Funders
- Damon Runyon Cancer Research Foundation
- Memorial Sloan-Kettering Cancer Center
- Pershing Square Sohn Cancer Research Alliance
- Break Through Cancer
- Cycle for Survival
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology
- National Cancer Institute