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

Lapo Alinari, Kiran V. Mahasenan, Fengting Yan, Vrajesh Karkhanis, Ji Hyun Chung, Emily M. Smith, Carl Quinion, Porsha L. Smith, Lisa Kim, John T. Patton, Rosa Lapalombella, Bo Yu, Yun Wu, Satavisha Roy, Alessandra De Leo, Stefano Pileri, Claudio Agostinelli, Leona Ayers, James E. Bradner, Selina Chen-KiangOlivier Elemento, Tasneem Motiwala, Sarmila Majumder, John C. Byrd, Samson Jacob, Said Sif, Chenglong Li, Robert A. Baiocchi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2530-2543
Number of pages14
JournalBlood
Volume125
Issue number16
DOIs
Publication statusPublished - Apr 16 2015

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Alinari, L., Mahasenan, K. V., Yan, F., Karkhanis, V., Chung, J. H., Smith, E. M., Quinion, C., Smith, P. L., Kim, L., Patton, J. T., Lapalombella, R., Yu, B., Wu, Y., Roy, S., De Leo, A., Pileri, S., Agostinelli, C., Ayers, L., Bradner, J. E., ... Baiocchi, R. A. (2015). Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation. Blood, 125(16), 2530-2543. https://doi.org/10.1182/blood-2014-12-619783