Abstract

Cancer is a hyper-proliferative clonal disease. Whether the proliferative state originates from the cell-of-origin or emerges later remains elusive. By tracking de novo transformation from normal hematopoietic progenitors expressing an acute myeloid leukemia (AML) oncogene MLL-AF9, we reveal that the cell cycle rate heterogeneity among granulocyte-macrophage progenitors (GMPs) determines their probability of transformation. An intrinsic fast cell cycle kinetics at the time of oncogene expression provide permissiveness for transformation, with the fastest cycling 3% of GMPs ([~]0.006% of bone marrow nucleated cells) acquiring malignancy with nearly 100% efficiency. Molecularly, we propose that MLL-AF9 preserves the gene expression of the cellular states in which it is expressed. As such, when expressed in the naturally-existing, rapidly-cycling myeloid progenitors, this cell state is perpetuated, yielding malignancy. Our work elucidates one of the earliest steps toward malignancy and suggests that modifying the cycling state of the cell-of-origin could be an effective approach to prevent malignancy.