Journal Article

DKFZ-2026-02615

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png TET2-driven activation of AGO2 links epigenetic remodeling to myeloid commitment and leukemia.

Lazarenkov, A. ; Valcárcel, G. ; Martinez, A. ; Berenguer, C. ; López-Rubio, A. V. ; Obiols, M. ; Fontanet, C. ; Barba, A. ; Rodríguez-Sevilla, J. J. ; Stik, G. ; Jeremias, I.DKFZ* ; Menendez, P. ; Sardina, J. L.

2026
Assoc. Washington, DC [u.a.]

Abstract: 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.

Keyword(s): Humans (MeSH) ; Dioxygenases (MeSH) ; Proto-Oncogene Proteins: metabolism (MeSH) ; Proto-Oncogene Proteins: genetics (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; DNA-Binding Proteins: genetics (MeSH) ; Epigenesis, Genetic (MeSH) ; Argonaute Proteins: genetics (MeSH) ; Argonaute Proteins: metabolism (MeSH) ; DNA Methylation (MeSH) ; Animals (MeSH) ; Enhancer Elements, Genetic (MeSH) ; Mice (MeSH) ; Leukemia, Myeloid, Acute: genetics (MeSH) ; Leukemia, Myeloid, Acute: metabolism (MeSH) ; Leukemia, Myeloid, Acute: pathology (MeSH) ; Chromatin: metabolism (MeSH) ; Chromatin: genetics (MeSH) ; Myeloid Cells: metabolism (MeSH) ; Cell Differentiation: genetics (MeSH) ; Dioxygenases ; TET2 protein, human ; Proto-Oncogene Proteins ; DNA-Binding Proteins ; Argonaute Proteins ; AGO2 protein, human ; Chromatin

Note: #DKTKZFB9#

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Contributing Institute(s):

1. DKTK Koordinierungsstelle München (MU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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