PRC2-Related Epigenetic Age Acceleration in Acute Myeloid Leukemia with DNMT3A and IDH2 Mutations.

Aging is closely linked to epigenetic remodeling, with DNA methylation (DNAm) emerging as a robust biomarker for estimating epigenetic age (EA) and quantifying senescence. Dysregulation of aging-associated DNAm has been implicated in diverse pathologies, including acute myeloid leukemia (AML). However, the effect of these epigenetic alterations in diseases and the underlying mechanism remains largely uncharacterized. Using causality-enriched epigenetic clocks, we identified that adaptive DNAm dynamics are sensitive to short-term therapeutic intervention in treating AML and may exhibit adaptive effects linked to better health outcomes. Subsequently, integrative genomic analysis showed significant associations between epigenetic aging and recurrent AML driver mutated genes, particularly DNMT3A and IDH2. The elevated adaptive aging associates with improved overall survival in cytogenetically normal AML harboring these mutations, highlighting its prognostic value in specific genomic contexts. Mechanistic analysis demonstrated that differentially methylated CpG sites in mutated gene-specific AML subtypes are enriched at polycomb repressive complex 2 (PRC2) targets. These findings link mutation-specific epigenetic aging, PRC2-mediated methylation dynamics, and AML pathogenesis, offering insights into how aging-related epigenetic dysregulation fosters malignant transformation. This study shows that AdaptAge can help reveal AML‑related DNAm dynamics when combined with genetic stratification, suggesting a path toward future biomarker development.