Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance Journal Article
| Authors: | Takao, S.; Morell, V.; Uni, M.; Slavit, A.; Rha, S.; Cheng, S.; Schmalbrock, L. K.; Brown, F. C.; Beneyto-Calabuig, S.; Koche, R. P.; Velten, L.; Kentsis, A. |
| Article Title: | Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance |
| 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. © The Author(s) 2025. |
| Keywords: | adult; unclassified drug; human cell; promoter region; genetics; leukemia, myeloid, acute; doxorubicin; cancer combination chemotherapy; nonhuman; chemotherapy; cytarabine; genetic analysis; mouse; animal; metabolism; animals; mice; gene expression; gene expression profiling; cell differentiation; drug effect; drug resistance; pathology; drug resistance, neoplasm; tumor marker; cancer resistance; rna binding protein; gene expression regulation; molecular cloning; gene rearrangement; neoplastic stem cells; epigenetics; chromatin; epigenesis, genetic; cell surface marker; leukemia cell; cancer stem cell; kruppel like factor; reactive oxygen metabolite; immunophenotyping; cell count; cell cycle g2 phase; upregulation; bone marrow cell; drug therapy; disease control; bone marrow transplantation; transcription factor fli 1; genetic epigenesis; genomic dna; induction chemotherapy; transcription factor ets; cell surface protein; gene expression regulation, leukemic; nucleoporin 98; cell; plasticity; transcription factor ap 1; mixed lineage leukemia protein; myeloid-lymphoid leukemia protein; acute myeloid leukemia; epigenetic inheritance; protein c jun; carboxyfluorescein diacetate succinimidyl ester; acyltransferase inhibitor; disease burden; humans; human; article; kruppel like factor 2; ccaat binding factor; venetoclax; gene set enrichment analysis; bone marrow derived mononuclear cell; design method; single cell rna seq; a 485; doxycycline hyclate; zfp36l2 protein |
| Journal Title: | Nature Communications |
| Volume: | 16 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-04-03 |
| Start Page: | 3196 |
| Language: | English |
| DOI: | 10.1038/s41467-025-58370-9 |
| PUBMED: | 40180954 |
| PROVIDER: | scopus |
| PMCID: | PMC11968996 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Alex Kentsis -- Source: Scopus |
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