Epigenetic dysregulation in acute myeloid leukemia.

Abstract

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy defined by the clonal expansion of undifferentiated myeloid blasts with a block in differentiation and aberrant self-renewal. While recurrent genomic mutations are well-documented in AML, epigenetic dysregulation has emerged as an equally pivotal driver of leukemogenesis, a notion corroborated by the frequent recurrence of mutations in epigenetic regulators. Leukemic cells exhibit pervasive epigenetic alterations-including abnormal DNA methylation patterns, dysregulated histone modification, disrupted chromatin architecture and RNA-based regulatory mechanisms -which collectively rewire gene expression programs. These changes silence key differentiation genes and sustain self-renewal pathways, enforcing the developmental arrest and hyper-proliferation that are the hallmarks of AML. Importantly, epigenetic aberrations in AML are not merely downstream consequences of genetic lesions but actively contribute to the malignant phenotype. Somatic mutations frequently target epigenetic regulators (for example, DNA methyltransferases or histone modifiers), and these lesions cooperate with other genetic alterations to initiate and maintain the leukemic clone. Together, these insights highlight epigenetic dysregulation as a central mechanism in AML pathogenesis.