Sustained MYC overexpression drives myeloid differentiation block and acquisition of leukemic phenotypes.

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 demonstrate that MYC overexpression from the endogenous locus, which maintains physiological regulation, results in a transient and reversible differentiation block that is insufficient for leukemogenesis. Instead, constitutive MYC overexpression from ectopic alleles, which results in a persistent block of differentiation, is necessary for driving and sustaining leukemia-associated phenotypes. These phenotypes result from the widespread disruption of epigenetic landscapes and transcription factor networks induced by MYC overexpression, underpinning differentiation arrest. Our findings shed new light on the mechanisms underlying MYC-induced malignant transformation and leukemogenesis, particularly the interplay between cellular differentiation and oncogenesis.