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 Stathias; Anna M Jermakowicz; Stephanie Duffort; Madhavi Tadi; Ezra Blumenthal; Samantha Newman; Ly Vu; Ye Xu; Fan Liu; Stephan C Schurer; Michael T McCabe; Ryan G Kruger; Mingjiang Xu; Feng-Chun Yang; Daniel G Tenen; Justin Watts; Francisco Vega; Stephen D Nimer

doi:10.1016/j.ccell.2018.05.007

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CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis

Journal article

Open access

Peer reviewed

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 Stathias, Anna M Jermakowicz, Stephanie Duffort, …

Cancer cell, Vol.33(6), pp.1111-1127.e5

2018-06-11

DOI: https://doi.org/10.1016/j.ccell.2018.05.007

PMID: 29894694

Abstract

AML

AML1-ETO

MLL-AF9

arginine methyltransferase

acute myeloid leukemia

CARM1

epigenetics

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. [Display omitted] •Conditional knockout of Carm1 has little effect on normal hematopoiesis•Loss of Carm1 abrogates the initiation and maintenance of AML in mouse models•CARM1 knockdown impairs cell-cycle progression and induces apoptosis in AML cells•A potent and selective CARM1 inhibitor impairs AML cell proliferation 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.

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.54 Molecular & Cell Biology - Genetics; 1.54.100 DNA Methylation
Web Of Science research areas: Cell Biology; Oncology
ESI research areas: Molecular Biology & Genetics

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Title: CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis
Creators: Sarah M Greenblatt - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Na Man - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Pierre-Jacques Hamard - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Takashi Asai - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Daniel Karl - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Concepcion Martinez - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Daniel Bilbao - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Vasileios Stathias - Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL 33136, USA
Anna M Jermakowicz - Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL 33136, USA
Stephanie Duffort - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Madhavi Tadi - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Ezra Blumenthal - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Samantha Newman - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Ly Vu - Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Ye Xu - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Fan Liu - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Stephan C Schurer - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Michael T McCabe - Cancer Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426, USA
Ryan G Kruger - Cancer Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426, USA
Mingjiang Xu - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Feng-Chun Yang - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Daniel G Tenen - Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA
Justin Watts - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Francisco Vega - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Stephen D Nimer - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Publication Details: Cancer cell, Vol.33(6), pp.1111-1127.e5
Publisher: Elsevier Inc
Academic Unit: Leadership Department; Miller School of Medicine; Biochemistry & Molecular Biology Research; Molecular and Cellular Pharmacology Research; Sylvester Comprehensive Cancer Center; UMMG Dept of Medicine - Hematology/Oncology
Language: English
Resource Type: Journal article
PMID: 29894694
Record Identifier: 991031577293202976