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

L Alinari, KV Mahasenan, F Yan… - Blood, The Journal …, 2015 - ashpublications.org
L Alinari, KV Mahasenan, F Yan, V Karkhanis, JH Chung, EM Smith, C Quinion, PL Smith…
Blood, The Journal of the American Society of Hematology, 2015ashpublications.org
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 …
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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