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

TitleSelective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation.
Publication TypeJournal Article
Year of Publication2015
AuthorsAlinari 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
Date Published2015 Apr 16
KeywordsAnimals, 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

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.

Alternate JournalBlood
PubMed ID25742700
PubMed Central IDPMC4400290
Grant ListR21 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