<p>Epigenetic allele diversity is linked to inferior prognosis in acute myeloid leukemia (AML). However, the source of epiallele heterogeneity in AML is unknown. Herein we analyzed epiallele diversity in a genetically and clinically annotated AML cohort. Notably, AML driver mutations linked to transcription factors and favorable outcome are associated with epigenetic destabilization in a defined set of susceptible loci. In contrast, AML subtypes linked to inferior prognosis manifest greater abundance and highly stochastic epiallele patterning. We report an epiallele outcome classifier supporting the link between epigenetic diversity and treatment failure. Mouse models with or mutations show that epiallele diversity is especially strongly induced by mutations, precedes transformation to AML, and is enhanced by cooperation between somatic mutations. Furthermore, epiallele complexity was partially reversed by epigenetic therapies in AML driven by /, suggesting that epigenetic therapy might function in part by reducing population complexity and fitness of AMLs. SIGNIFICANCE: We show for the first time that epigenetic clonality is directly linked to specific mutations and that epigenetic allele diversity precedes and potentially contributes to malignant transformation. Furthermore, epigenetic clonality is reversible with epigenetic therapy agents..</p>