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Cell Rep. 2013 Dec 26;5(6):1625-38. doi: 10.1016/j.celrep.2013.11.025. Epub 2013 Dec 12.

PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex.

Author information

1
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
2
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
3
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
4
Department of Pathology, the University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
5
Molecular Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
6
Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
7
Cancer Center, Montefiore Medical Center-North Division, Bronx, NY 10466, USA.
8
Department of Medicine, Hematology Oncology Division, Weill Cornell Medical College, New York, NY 10065, USA.
9
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Department of Biochemistry & Molecular Genetics, University of Alabama, Birmingham, AL 35294, USA. Electronic address: zhaox88@uab.edu.
10
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL 33136, USA; Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL 33136, USA. Electronic address: snimer@med.miami.edu.

Abstract

Defining the role of epigenetic regulators in hematopoiesis has become critically important, because recurrent mutations or aberrant expression of these genes has been identified in both myeloid and lymphoid hematological malignancies. We found that PRMT4, a type I arginine methyltransferase whose function in normal and malignant hematopoiesis is unknown, is overexpressed in acute myelogenous leukemia patient samples. Overexpression of PRMT4 blocks the myeloid differentiation of human stem/progenitor cells (HSPCs), whereas its knockdown is sufficient to induce myeloid differentiation of HSPCs. We demonstrated that PRMT4 represses the expression of miR-223 in HSPCs via the methylation of RUNX1, which triggers the assembly of a multiprotein repressor complex that includes DPF2. As part of the feedback loop, PRMT4 expression is repressed posttranscriptionally by miR-223. Depletion of PRMT4 results in differentiation of myeloid leukemia cells in vitro and their decreased proliferation in vivo. Thus, targeting PRMT4 holds potential as a novel therapy for acute myelogenous leukemia.

PMID:
24332853
PMCID:
PMC4073674
DOI:
10.1016/j.celrep.2013.11.025
[Indexed for MEDLINE]
Free PMC Article
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