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

Ly P Vu; Fabiana Perna; Lan Wang; Francesca Voza; Maria E Figueroa; Paul Tempst; Hediye Erdjument-Bromage; Rui Gao; Sisi Chen; Elisabeth Paietta; Tony Deblasio; Ari Melnick; Yan Liu; Xinyang Zhao; Stephen D Nimer

doi:10.1016/j.celrep.2013.11.025

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

Journal article

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Peer reviewed

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

Ly P Vu, Fabiana Perna, Lan Wang, Francesca Voza, Maria E Figueroa, Paul Tempst, Hediye Erdjument-Bromage, Rui Gao, Sisi Chen, Elisabeth Paietta, …

Cell reports (Cambridge), Vol.5(6), pp.1625-1638

2013-12-26

DOI: https://doi.org/10.1016/j.celrep.2013.11.025

PMCID: PMC4073674

PMID: 24332853

Abstract

Myeloid Progenitor Cells - metabolism

Core Binding Factor Alpha 2 Subunit - metabolism

Epigenetic Repression

RNA Processing, Post-Transcriptional

Humans

MicroRNAs - metabolism

Protein-Arginine N-Methyltransferases - metabolism

DNA-Binding Proteins - metabolism

Animals

Hematopoiesis

Cell Line, Tumor

Myeloid Progenitor Cells - cytology

Protein Binding

Mice

MicroRNAs - genetics

Protein-Arginine N-Methyltransferases - genetics

Methylation

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.

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Collaboration types: Domestic 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
ESI research areas: Molecular Biology & Genetics

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Title: PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex
Creators: Ly P Vu - 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
Fabiana Perna - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Lan Wang - 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
Francesca Voza - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Maria E Figueroa - Department of Pathology, the University of Michigan Medical School, Ann Arbor, MI, 48109, USA
Paul Tempst - Molecular Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Hediye Erdjument-Bromage - Molecular Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Rui Gao - Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Sisi Chen - Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Elisabeth Paietta - Cancer Center, Montefiore Medical Center-North Division, Bronx, NY 10466, USA
Tony Deblasio - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Ari Melnick - Department of Medicine, Hematology Oncology Division, Weill Cornell Medical College, New York, NY 10065, USA
Yan Liu - Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Xinyang Zhao - 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
Stephen D Nimer - 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
Publication Details: Cell reports (Cambridge), Vol.5(6), pp.1625-1638
Publisher: United States
Grant note: U10 CA021115 / NCI NIH HHS P30 CA08748 / NCI NIH HHS R01CA166835 / NCI NIH HHS U10 CA037403 / NCI NIH HHS R01 CA166835 / NCI NIH HHS U24 CA114737 / NCI NIH HHS P30 CA008748 / NCI NIH HHS
Academic Unit: Leadership Department; Miller School of Medicine; Sylvester Comprehensive Cancer Center; UMMG Dept of Human Genetics - Clinical and Translational Genetics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 24332853
PMCID: PMC4073674
Record Identifier: 991031561455002976