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

Lazarenkov, A.; Valcarcel, G.; Martinez, A.; Berenguer, C.; Lopez-Rubio, A. V.; Obiols, M.; Fontanet, C.; Rodriguez-Sevilla, J. J.; Stik, G.; Jeremias, I.; Menendez, P.; Sardina, J. L.

doi:10.64898/2026.04.23.719229

bioRxiv · 10.64898/2026.04.23.719229

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

Lazarenkov, A.·Valcarcel, G.·Martinez, A.·Berenguer, C.·Lopez-Rubio, A. V.·Obiols, M.·Fontanet, C.·Rodriguez-Sevilla, J. J.·Stik, G.·Jeremias, I.·Menendez, P.·Sardina, J. L.

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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, 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 an AGO2 myeloid-specific intragenic enhancer that is frequently hypermethylated in TET2-mutant AML patients. 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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Lazarenkov, A., Valcarcel, G., Martinez, A., Berenguer, C., Lopez-Rubio, A. V., Obiols, M., Fontanet, C., Rodriguez-Sevilla, J. J., Stik, G., Jeremias, I., Menendez, P., Sardina, J. L.. 2026-04-25. TET2-driven activation of AGO2 links epigenetic remodeling to myeloid commitment and leukemia. https://doi.org/10.64898/2026.04.23.719229

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