Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation.
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.
Division of Hematology, Department of Internal Medicine.
Lapo
L
Alinari
Division of Medicinal Chemistry and Pharmacognosy, and.
Kiran V
KV
Mahasenan
Division of Hematology, Department of Internal Medicine.
Fengting
F
Yan
Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH;
Vrajesh
V
Karkhanis
Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH;
Ji-Hyun
JH
Chung
Division of Hematology, Department of Internal Medicine.
Emily M
EM
Smith
Division of Hematology, Department of Internal Medicine.
Carl
C
Quinion
Division of Hematology, Department of Internal Medicine.
Porsha L
PL
Smith
Division of Hematology, Department of Internal Medicine.
Lisa
L
Kim
Division of Hematology, Department of Internal Medicine.
John T
JT
Patton
Division of Hematology, Department of Internal Medicine.
Rosa
R
Lapalombella
Division of Hematology, Department of Internal Medicine.
Bo
B
Yu
Division of Hematology, Department of Internal Medicine.
Yun
Y
Wu
Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH;
Satavisha
S
Roy
Department of Public Health and Infectious Diseases, University La Sapienza, Rome, Italy;
Alessandra
A
De Leo
Hematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy;
Stefano
S
Pileri
Hematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy;
Claudio
C
Agostinelli
Department of Pathology, The Ohio State University, Columbus, OH;
Leona
L
Ayers
Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
James E
JE
Bradner
Department of Pathology and Laboratory Medicine, and.
Selina
S
Chen-Kiang
Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY; and.
Olivier
O
Elemento
Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH;
Tasneem
T
Motiwala
Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH;
Sarmila
S
Majumder
Division of Hematology, Department of Internal Medicine, Division of Medicinal Chemistry and Pharmacognosy, and.
John C
JC
Byrd
Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH;
Samson
S
Jacob
Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha, Qatar.
Said
S
Sif
Division of Medicinal Chemistry and Pharmacognosy, and.
Chenglong
C
Li
Division of Hematology, Department of Internal Medicine.
Robert A
RA
Baiocchi
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D015153:Blotting, Western; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004854:Herpesvirus 4, Human / Q000502:physiology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000821:virology; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054852:Small Molecule Libraries / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000099186:Histone Deacetylase 3
D004791:Enzyme Inhibitors; D006655:Histone Deacetylases; D035683:MicroRNAs; D011484:Protein-Arginine N-Methyltransferases; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D054852:Small Molecule Libraries; D051996:Transcription Factor RelA; D025521:Tumor Suppressor Proteins; D000099186:Histone Deacetylase 3; C541492:MIRN96 microRNA, human; C412123:ST7 protein, human; C400529:PRMT5 protein, human; C516888:PTPRO protein, human