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

Xiaoqing Lu, Tharu Fernando, Chen Lossos, Nevin Yusufova, Fan Liu, Lorena Fontán, Matthew Durant, Huimin Geng, Jacob Melnick, Yuan Luo, Francisco Vega, Vincent Moy, Giorgio Inghirami, Stephen Nimer, Ari M. Melnick and Izidore S. Lossos

Key points

  • PRMT5 methylates and is needed for the full transcriptional repressive activity of BCL6 and is necessary for germinal center formation.

  • Concomitant inhibition of both BCL6 and PRMT5 exhibits synergistic killing of BCL6-expressing lymphoma cells.

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 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 co-targeting PRMT5 and BCL6 in lymphoma.

  • Submitted February 5, 2018.
  • Accepted July 24, 2018.