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

Blood. 2019 Aug 15;134(7):614-625. doi: 10.1182/blood.2018888255. Epub 2019 Jul 3.

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). Prdm16s expression in megakaryocyte-erythroid progenitors (MEPs), which normally lack the potential to generate granulomonocytic cells, caused AML by converting MEPs into LSCs. Prdm16s 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 Prdm16s-induced leukemia. Ablating PU.1 attenuated leukemogenesis and reinstated the megakaryocytic/erythroid potential of leukemic MEPs in mouse models and human AML with PRDM16 rearrangement. Thus, oncogenic PRDM16 s expression gives MEPs an LSC fate by activating myeloid gene regulatory networks.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / pathology*
  • DNA-Binding Proteins / genetics*
  • Gene Expression Regulation, Leukemic
  • Gene Regulatory Networks
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology*
  • Megakaryocyte-Erythroid Progenitor Cells / metabolism
  • Megakaryocyte-Erythroid Progenitor Cells / pathology*
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins / genetics
  • Trans-Activators / genetics
  • Transcription Factors / genetics*
  • Translocation, Genetic

Substances

  • DNA-Binding Proteins
  • PRDM16 protein, human
  • Prdm16 protein, mouse
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Transcription Factors
  • proto-oncogene protein Spi-1