CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis

Sarah M. Greenblatt, Na Man, Pierre Jacques Hamard, Takashi Asai, Daniel Karl, Concepcion Martinez, Daniel Bilbao, Vasileios Stathais, Anna McGrew-Jermacowicz, Stephanie Duffort, Madhavi Tadi, Ezra Blumenthal, Samantha Newman, Ly Vu, Ye Xu, Fan Liu, Stephan C Schuerer, Michael T. McCabe, Ryan G. Kruger, Mingjiang XuFeng-Chun Yang, Daniel Tenen, Justin Watts, Francisco Vega, Stephen D Nimer

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Chromatin-modifying enzymes, and specifically the protein arginine methyltransferases (PRMTs), have emerged as important targets in cancer. Here, we investigated the role of CARM1 in normal and malignant hematopoiesis. Using conditional knockout mice, we show that loss of CARM1 has little effect on normal hematopoiesis. Strikingly, knockout of Carm1 abrogates both the initiation and maintenance of acute myeloid leukemia (AML) driven by oncogenic transcription factors. We show that CARM1 knockdown impairs cell-cycle progression, promotes myeloid differentiation, and ultimately induces apoptosis. Finally, we utilize a selective, small-molecule inhibitor of CARM1 to validate the efficacy of CARM1 inhibition in leukemia cells in vitro and in vivo. Collectively, this work suggests that targeting CARM1 may be an effective therapeutic strategy for AML. Greenblatt et al. show that loss of the protein arginine methyltransfersase CARM1 minimally impacts normal hematopoiesis but strongly impairs leukemogenesis by regulating cell-cycle progression, myeloid differentiation, and apoptosis. Targeting CARM1 reduces AML growth in primary patient samples and mouse models.

Original languageEnglish (US)
Pages (from-to)1111-1127.e5
JournalCancer Cell
Volume33
Issue number6
DOIs
StatePublished - Jun 11 2018

Keywords

  • acute myeloid leukemia
  • AML
  • AML1-ETO
  • arginine methyltransferase
  • CARM1
  • epigenetics
  • MLL-AF9

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Greenblatt, S. M., Man, N., Hamard, P. J., Asai, T., Karl, D., Martinez, C., Bilbao, D., Stathais, V., McGrew-Jermacowicz, A., Duffort, S., Tadi, M., Blumenthal, E., Newman, S., Vu, L., Xu, Y., Liu, F., Schuerer, S. C., McCabe, M. T., Kruger, R. G., ... Nimer, S. D. (2018). CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis. Cancer Cell, 33(6), 1111-1127.e5. https://doi.org/10.1016/j.ccell.2018.05.007