# PRC2‐Related Epigenetic Age Acceleration in Acute Myeloid Leukemia with DNMT3A and IDH2 Mutations

## TL;DR

This study explores how epigenetic aging, influenced by DNA methylation, relates to acute myeloid leukemia, particularly in cases with DNMT3A and IDH2 mutations.

## Contribution

The study introduces causality-enriched epigenetic clocks to reveal mutation-specific DNA methylation dynamics in AML.

## Key findings

- Adaptive DNA methylation dynamics are sensitive to short-term therapeutic intervention in AML.
- Epigenetic aging is significantly associated with DNMT3A and IDH2 mutations in AML.
- Differentially methylated sites in mutated AML subtypes are enriched at PRC2 targets.

## Abstract

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.

This study reveals causality‑enriched epigenetic clocks offer additional insight into acute myeloid leukemia (AML) specific DNA methylation remodeling, particularly when integrated with genetic stratification, like DNMT3A or IDH2 mutations. AdaptAge showed subgroup‑specific associations with survival and appeared responsive to treatment‑related changes, links this association with the altered methylation at polycomb repressive complex 2 (PRC2) targets.