Beyond the DNA sequence: mapping the dynamic epigenetic landscape for risk stratification and therapeutic...

Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy where traditional DNA sequence-based classification fails to fully explain clinical outcomes. This review explores the dynamic and multifaceted role of the epigenome as a critical driver of leukemogenesis, progression, and therapeutic resistance. We detail how disruptions in DNA methylation, histone modifications, chromatin architecture, and non-coding RNAs create a complex regulatory landscape that transcends genetic alterations. We highlight the emergence of single-cell multi-omics technologies, which are resolving intratumoral heterogeneity and uncovering the epigenetic signatures of leukemic stem cells. Furthermore, we discuss the significant translational potential of these discoveries, including the development of epigenetic biomarkers for refined risk stratification, minimal residual disease (MRD) monitoring, and predicting response to novel epigenetic therapies like menin and LSD1 inhibitors. Integrating these dynamic epigenetic layers into clinical decision-making promises to usher in a new era of precision medicine, ultimately improving prognostic accuracy and therapeutic outcomes for AML patients.