Title | Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Alinari L, Mahasenan KV, Yan F, Karkhanis V, Chung J-H, Smith EM, Quinion C, Smith PL, Kim L, Patton JT, Lapalombella R, Yu B, Wu Y, Roy S, De Leo A, Pileri S, Agostinelli C, Ayers L, Bradner JE, Chen-Kiang S, Elemento O, Motiwala T, Majumder S, Byrd JC, Jacob S, Sif S, Li C, Baiocchi RA |
Journal | Blood |
Volume | 125 |
Issue | 16 |
Pagination | 2530-43 |
Date Published | 2015 Apr 16 |
ISSN | 1528-0020 |
Keywords | Animals, B-Lymphocytes, Blotting, Western, Cell Line, Transformed, Cell Transformation, Viral, Cells, Cultured, Enzyme Inhibitors, Herpesvirus 4, Human, Histone Deacetylases, Host-Pathogen Interactions, Humans, Lymphoma, Mice, SCID, MicroRNAs, Microscopy, Confocal, Protein-Arginine N-Methyltransferases, Receptor-Like Protein Tyrosine Phosphatases, Class 3, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Small Molecule Libraries, Transcription Factor RelA, Transcriptome, Tumor Suppressor Proteins |
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. |
DOI | 10.1182/blood-2014-12-619783 |
Alternate Journal | Blood |
PubMed ID | 25742700 |
PubMed Central ID | PMC4400290 |
Grant List | R21 NS071346 / NS / NINDS NIH HHS / United States R21NS071346 / NS / NINDS NIH HHS / United States R01CA116093 / CA / NCI NIH HHS / United States R01 CA116093 / CA / NCI NIH HHS / United States T15 LM011270 / LM / NLM NIH HHS / United States |