PRDM16s transforms megakaryocyte-erythroid progenitors into myeloid leukemia–initiating cells

Abstract

Oncogenic mutations confer on 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). <i>Prdm16s</i> expression in megakaryocyte-erythroid progenitors (MEPs), which normally lack the potential to generate granulomonocytic cells, caused AML by converting MEPs into LSCs. <i>Prdm16s</i> blocked megakaryocytic/erythroid potential by interacting with super enhancers and activating myeloid master regulators, including PU.1. A CRISPR dropout screen confirmed that PU.1 is required for <i>Prdm16s</i>-induced leukemia. Ablating PU.1 attenuated leukemogenesis and reinstated the megakaryocytic/erythroid potential of leukemic MEPs in mouse models and human AML with <i>PRDM16</i> rearrangement. Thus, oncogenic <i>PRDM16</i> <i>s</i> expression gives MEPs an LSC fate by activating myeloid gene regulatory networks.