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, Sarah & Man, Na & Hamard, Pierre-Jacques & Asai, Takashi & Karl, Daniel & Martinez, Concepcion & Bilbao, Daniel & Stathais, Vasileios & McGrew-Jermacowicz, Anna & Duffort, Stephanie & Tadi, Madhavi & Blumenthal, Ezra & Newman, Samantha & Vu, Ly & Xu, Ye & Liu, Fan & C Schürer, Stephan & T McCabe, Michael & Kruger, Ryan & Nimer, Stephen. (June 11, 2018). CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis. Cancer cell. 33. 1111-1127.e5. 10.1016/j.ccell.2018.05.007.
Keywords: AML; AML1-ETO; CARM1; MLL-AF9; acute myeloid leukemia; arginine methyltransferase; epigenetics