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Lazarenkov, A.* ; Valcárcel, G.* ; Martínez-Moreno, A.* ; Berenguer, C.* ; López-Rubio, A.V.* ; Obiols, M.* ; Fontanet, C.* ; Barbă, A.* ; Rodríguez‐Sevilla, J.J.* ; Stik, G.* ; Jeremias, I. ; Menéndez, P.R.* ; Sardina, J.L.*

TET2-driven activation of AGO2 links epigenetic remodeling to myeloid commitment and leukemia.

Sci. Adv. 12:eaee5701 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
DNA methylation dynamics shape hematopoietic differentiation and leukemogenesis, yet how the dioxygenase TET2-frequently mutated in myeloid malignancies-directs lineage-specific regulatory programs remains unclear. Here, we integrated DNA methylation, chromatin accessibility, three-dimensional (3D) genome architecture, transcriptional profiling, and TET2 chromatin occupancy to define TET2-dependent control of human myeloid commitment. We found that TET2-bound regulatory regions gain short- and long-range chromatin interactions and that a distinct subset of distal, enhancer-enriched sites undergoes TET2-driven demethylation and activation. Among these, we identified and functionally validated an AGO2 myeloid-specific intragenic enhancer that is frequently hypermethylated in patients with TET2-mutant acute myeloid leukemia. AGO2 expression stratifies patient survival, and AGO2 depletion abrogates leukemic engraftment in vivo. These findings uncover a TET2-AGO2 regulatory axis that integrates epigenetic remodeling, 3D genome reorganization, and leukemic fitness, and they highlight AGO2 as a potential biomarker and therapeutic target in myeloid leukemia.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Zeitschrift Science Advances
Quellenangaben Band: 12, Heft: 43, Seiten: , Artikelnummer: eaee5701 Supplement: ,
Verlag American Association for the Advancement of Science (AAAS)
Verlagsort Washington, DC [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Apoptosis in Hematopoetic Stem Cells (AHS)