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

Tianyuan Hu, Kiyomi Morita, Matthew C. Hill, Yajian Jiang, Ayumi Kitano, Yusuke Saito, Feng Wang, Xizeng Mao, Kevin A. Hoegenauer, Kazuhiro Morishita, James F. Martin, P. Andrew Futreal, Koichi Takahashi, Daisuke Nakada

Research output: Contribution to journalArticle

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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 PRDM16s expression gives MEPs an LSC fate by activating myeloid gene regulatory networks.

Original languageEnglish (US)
Pages (from-to)614-625
Number of pages12
JournalBlood
Volume134
Issue number7
DOIs
StatePublished - Aug 15 2019

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Hu, T., Morita, K., Hill, M. C., Jiang, Y., Kitano, A., Saito, Y., Wang, F., Mao, X., Hoegenauer, K. A., Morishita, K., Martin, J. F., Futreal, P. A., Takahashi, K., & Nakada, D. (2019). PRDM16s transforms megakaryocyte-erythroid progenitors into myeloid leukemia-initiating cells. Blood, 134(7), 614-625. https://doi.org/10.1182/blood.2018888255