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

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.