CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis

Cancer Cell. 2018 Jun 11;33(6):1111-1127.e5. doi: 10.1016/j.ccell.2018.05.007.

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.

Keywords: AML; AML1-ETO; CARM1; MLL-AF9; acute myeloid leukemia; arginine methyltransferase; epigenetics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Disease
  • Animals
  • Apoptosis / genetics
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic*
  • Hematopoiesis / genetics*
  • Humans
  • Kaplan-Meier Estimate
  • Leukemia, Myeloid / genetics*
  • Leukemia, Myeloid / metabolism
  • Leukemia, Myeloid / pathology
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Mice, Transgenic
  • Protein-Arginine N-Methyltransferases / genetics*
  • Protein-Arginine N-Methyltransferases / metabolism

Substances

  • Protein-Arginine N-Methyltransferases
  • coactivator-associated arginine methyltransferase 1