title: PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex.
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.
authors: 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.
authors: Ly P
authors: LP
authors: Vu
authors: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Fabiana
authors: F
authors: Perna
authors: 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.
authors: Lan
authors: L
authors: Wang
authors: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Francesca
authors: F
authors: Voza
authors: Department of Pathology, the University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
authors: Maria E
authors: ME
authors: Figueroa
authors: Molecular Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Paul
authors: P
authors: Tempst
authors: Molecular Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Hediye
authors: H
authors: Erdjument-Bromage
authors: Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: Rui
authors: R
authors: Gao
authors: Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: Sisi
authors: S
authors: Chen
authors: Cancer Center, Montefiore Medical Center-North Division, Bronx, NY 10466, USA.
authors: Elisabeth
authors: E
authors: Paietta
authors: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Tony
authors: T
authors: Deblasio
authors: Department of Medicine, Hematology Oncology Division, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Ari
authors: A
authors: Melnick
authors: Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: Yan
authors: Y
authors: Liu
authors: 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.
authors: Xinyang
authors: X
authors: Zhao
authors: 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.
authors: Stephen D
authors: SD
authors: Nimer
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D063185:Epigenetic Repression; D006410:Hematopoiesis; D006801:Humans; D008745:Methylation; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D014157:Transcription Factors
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D011484:Protein-Arginine N-Methyltransferases; D014157:Transcription Factors; C113581:DPF2 protein, human; C525067:MIR223, human; C493728:RUNX1 protein, human; C119966:coactivator-associated arginine methyltransferase 1