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Blood. 2018 Nov 8;132(19):2026-2039. doi: 10.1182/blood-2018-02-831438. Epub 2018 Aug 6.

PRMT5 interacts with the BCL6 oncoprotein and is required for germinal center formation and lymphoma cell survival.

Author information

1
Division of Hematology, Department of Medicine, University of Miami, Miami, FL.
2
Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY.
3
Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL.
4
Sylvester Comprehensive Cancer Center, Miami, FL.
5
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA.
6
Department of Pathology and.
7
Department of Physics and Biophysics, University of Miami, Miami, FL.
8
Department of Pathology and Laboratory of Medicine, Weill Cornell Medical College, New York, NY; and.
9
Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL.

Abstract

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.

PMID:
30082494
PMCID:
PMC6236466
[Available on 2019-11-08]
DOI:
10.1182/blood-2018-02-831438
[Indexed for MEDLINE]

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