2. Academic Validation
  3. Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation

Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation

  • Blood. 2015 Apr 16;125(16):2530-43. doi: 10.1182/blood-2014-12-619783.
Lapo Alinari 1,  Kiran V Mahasenan 2,  Fengting Yan 1,  Vrajesh Karkhanis 3,  Ji-Hyun Chung 3,  Emily M Smith 1,  Carl Quinion 1,  Porsha L Smith 1,  Lisa Kim 1,  John T Patton 1,  Rosa Lapalombella 1,  Bo Yu 1,  Yun Wu 1,  Satavisha Roy 3,  Alessandra De Leo 4,  Stefano Pileri 5,  Claudio Agostinelli 5,  Leona Ayers 6,  James E Bradner 7,  Selina Chen-Kiang 8,  Olivier Elemento 9,  Tasneem Motiwala 3,  Sarmila Majumder 3,  John C Byrd 10,  Samson Jacob 3,  Said Sif 11,  Chenglong Li 2,  Robert A Baiocchi 1
Affiliations

Affiliations

  • 1 Division of Hematology, Department of Internal Medicine.
  • 2 Division of Medicinal Chemistry and Pharmacognosy, and.
  • 3 Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH;
  • 4 Department of Public Health and Infectious Diseases, University La Sapienza, Rome, Italy;
  • 5 Hematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy;
  • 6 Department of Pathology, The Ohio State University, Columbus, OH;
  • 7 Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
  • 8 Department of Pathology and Laboratory Medicine, and.
  • 9 Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY; and.
  • 10 Division of Hematology, Department of Internal Medicine, Division of Medicinal Chemistry and Pharmacognosy, and.
  • 11 Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha, Qatar.
PMID: 25742700 DOI: 10.1182/blood-2014-12-619783
Abstract

Epigenetic events that are essential drivers of lymphocyte transformation remain incompletely characterized. We used models of Epstein-Barr virus (EBV)-induced B-cell transformation to document the relevance of protein arginine methyltransferase 5 (PRMT5) to regulation of epigenetic-repressive marks during lymphomagenesis. EBV(+) lymphomas and transformed cell lines exhibited abundant expression of PRMT5, a type II PRMT Enzyme that promotes transcriptional silencing of target genes by methylating arginine residues on histone tails. PRMT5 expression was limited to EBV-transformed cells, not resting or activated B lymphocytes, validating it as an ideal therapeutic target. We developed a first-in-class, small-molecule PRMT5 Inhibitor that blocked EBV-driven B-lymphocyte transformation and survival while leaving normal B cells unaffected. Inhibition of PRMT5 led to lost recruitment of a PRMT5/p65/HDAC3-repressive complex on the miR96 promoter, restored miR96 expression, and PRMT5 downregulation. RNA-sequencing and chromatin immunoprecipitation experiments identified several tumor suppressor genes, including the protein tyrosine Phosphatase gene PTPROt, which became silenced during EBV-driven B-cell transformation. Enhanced PTPROt expression following PRMT5 inhibition led to dephosphorylation of kinases that regulate B-cell receptor signaling. We conclude that PRMT5 is critical to EBV-driven B-cell transformation and maintenance of the malignant phenotype, and that PRMT5 inhibition shows promise as a novel therapeutic approach for B-cell lymphomas.

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