TY - JOUR
T1 - CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis
AU - Greenblatt, Sarah M.
AU - Man, Na
AU - Hamard, Pierre Jacques
AU - Asai, Takashi
AU - Karl, Daniel
AU - Martinez, Concepcion
AU - Bilbao, Daniel
AU - Stathais, Vasileios
AU - McGrew-Jermacowicz, Anna
AU - Duffort, Stephanie
AU - Tadi, Madhavi
AU - Blumenthal, Ezra
AU - Newman, Samantha
AU - Vu, Ly
AU - Xu, Ye
AU - Liu, Fan
AU - Schurer, Stephan C.
AU - McCabe, Michael T.
AU - Kruger, Ryan G.
AU - Xu, Mingjiang
AU - Yang, Feng Chun
AU - Tenen, Daniel
AU - Watts, Justin
AU - Vega, Francisco
AU - Nimer, Stephen D.
N1 - Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/6/11
Y1 - 2018/6/11
N2 - 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.
AB - 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.
KW - AML
KW - AML1-ETO
KW - CARM1
KW - MLL-AF9
KW - acute myeloid leukemia
KW - arginine methyltransferase
KW - epigenetics
UR - http://www.scopus.com/inward/record.url?scp=85047524038&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047524038&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2018.05.007
DO - 10.1016/j.ccell.2018.05.007
M3 - Article
C2 - 29894694
AN - SCOPUS:85047524038
SN - 1535-6108
VL - 33
SP - 1111-1127.e5
JO - Cancer Cell
JF - Cancer Cell
IS - 6
ER -