PRDM16s transforms megakaryocyte-erythroid progenitors to acute myeloid leukemia-initiating cells

Oncogenic mutations confer cells the ability to propagate indefinitely, but whether oncogenes alter the cell fate of these cells is unknown. Here, we show that the transcriptional regulator PRDM16s causes oncogenic fate conversion by transforming cells fated to form platelets and erythrocytes into myeloid leukemia stem cells (LSCs). Prdm16s expression in megakaryocyte-erythroid progenitors (MEPs), which normally lack the potential to generate granulo-monocytic cells, caused AML by converting MEPs to LSCs. Prdm16s blocked megakaryocytic/erythroid potential by interacting with super enhancers and activating myeloid master regulators, including PU.1. A CRISPR-dropout screen identified that PU.1 is required for Prdm16s -induced leukemia. Ablating PU.1 attenuated leukemogenesis and reinstated the megakaryocytic/erythroid potential of leukemic-MEPs in mouse models and in human AML with PRDM16 rearrangement. Thus, oncogenic PRDM16 expression converts MEPs to an LSC fate by activating myeloid gene regulatory networks.