TitlePRMT5 interacts with the BCL6 oncoprotein and is required for germinal center formation and lymphoma cell survival.
Publication TypeJournal Article
Year of Publication2018
AuthorsLu, Xiaoqing, Fernando Tharu M., Lossos Chen, Yusufova Nevin, Liu Fan, Fontan Lorena, Durant Matthew, Geng Huimin, Melnick Jacob, Luo Yuan, Vega Francisco, Moy Vincent, Inghirami Giorgio, Nimer Stephen, Melnick Ari M., and Lossos Izidore S.
JournalBlood
Volume132
Issue19
Pagination2026-2039
Date Published2018 11 08
ISSN1528-0020
KeywordsAnimals, Cell Line, Tumor, Cell Proliferation, Cell Survival, Gene Expression Regulation, Neoplastic, Germinal Center, Humans, Lymphoma, Mice, Knockout, Protein Interaction Maps, Protein-Arginine N-Methyltransferases, Proto-Oncogene Proteins c-bcl-6
Abstract

<p>The germinal center (GC) reaction plays an important role in generating humoral immunity and is believed to give rise to most B-cell lymphomas. GC entry and exit are tightly regulated processes, controlled by the actions of transcription factors such as BCL6. Herein, we demonstrate that protein arginine methyltransferase 5 (PRMT5), a symmetric dimethyl arginine methyltransferase, is also necessary for GC formation and affinity maturation. PRMT5 contributes to GC formation and affinity maturation at least in part through its direct interaction with and methylation of BCL6 at arginine 305 (R305), a modification necessary for the full transcriptional repressive effects of BCL6. Inhibition of PRMT5 in B-cell lymphoma lines led to significant upregulation of BCL6 target genes, and the concomitant inhibition of both BCL6 and PRMT5 exhibited synergistic killing of BCL6-expressing lymphoma cells. Our studies identify PRMT5 as a novel regulator of the GC reaction and highlight the mechanistic rationale of cotargeting PRMT5 and BCL6 in lymphoma.</p>

DOI10.1182/blood-2018-02-831438
Alternate JournalBlood
PubMed ID30082494
PubMed Central IDPMC6236466
Grant ListP50 CA192937 / CA / NCI NIH HHS / United States
R01 CA155226 / CA / NCI NIH HHS / United States
R35 CA220499 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States