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Dysregulation of aging\u2010associated 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\u2010enriched epigenetic clocks, we identified that adaptive DNAm dynamics are sensitive to short\u2010term 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\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    and\n                    <jats:italic>IDH2<\/jats:italic>\n                    . 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\u2010specific AML subtypes are enriched at polycomb repressive complex 2 (PRC2) targets. These findings link mutation\u2010specific epigenetic aging, PRC2\u2010mediated methylation dynamics, and AML pathogenesis, offering insights into how aging\u2010related epigenetic dysregulation fosters malignant transformation. This study shows that AdaptAge can help reveal AML\u2011related DNAm dynamics when combined with genetic stratification, suggesting a path toward future biomarker development.\n                  <\/jats:p>","DOI":"10.1002\/adbi.202500710","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T10:36:58Z","timestamp":1768905418000},"source":"Crossref","is-referenced-by-count":3,"title":["PRC2\u2010Related Epigenetic Age Acceleration in Acute Myeloid Leukemia with\n                    <i>DNMT3A<\/i>\n                    and\n                    <i>IDH2<\/i>\n                    Mutations"],"prefix":"10.1002","volume":"10","author":[{"given":"Zhengyi","family":"Yan","sequence":"first","affiliation":[{"name":"School of Medicine The Chinese University of Hong Kong  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luowei","family":"Yuan","sequence":"additional","affiliation":[{"name":"School of Medicine The Chinese University of 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