Ectopic MYC Expression Reprograms Epigenetic Landscapes and Transcription Factor Networks to Drive Differentiation Block and Malignant Transformation in AML [ATAC-seq]

Overexpression of MYC is a common convergent consequence of genetic driver mutations in acute myeloid leukemia (AML). However, despite extensive research, the mechanisms by which this proto-oncogene promotes leukemogenesis remain incompletely understood. Here, we developed models of deregulated MYC expression in human pluripotent stem cell (hPSC)-derived myelopoiesis. We show that MYC overexpression from the endogenous locus maintaining physiological regulation is insufficient for leukemogenesis. Rather, constitutive MYC overexpression from ectopic alleles is necessary for driving and sustaining leukemia-associated phenotypes. These phenotypes depend on the widespread disruption of epigenetic landscapes imposed by MYC overexpression, which in turn underlies a differentiation arrest and dysregulation of the BACH1 transcription factor network, identified here as a mediator of these changes. Our findings shed new light into the mechanisms underlying MYC-induced malignant transformation and leukemogenesis, suggesting novel therapeutic targets for AML.