PRMT5 is upregulated by B-cell receptor signaling and forms a positive-feedback loop with PI3K/AKT in lymphoma cells

Fen Zhu, Hui Guo, Paul D. Bates, Shanxiang Zhang, Hui Zhang, Krystle J. Nomie, Yangguang Li, Li Lu, Kaitlyn R. Seibold, Fangyu Wang, Ian Rumball, Hunter Cameron, Nguyet M. Hoang, David T. Yang, Wei Xu, Liang Zhang, Michael Wang, Christian M. Capitini, Lixin Rui

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

PRMT5, which regulates gene expression by symmetric dimethylation of histones and non-histone target proteins, is overexpressed and plays a pathogenic role in many cancers. In diffuse large B cell lymphoma (DLBCL), the mechanisms of PRMT5 dysregulation and its role in lymphomagenesis remain largely unknown. Here we demonstrate that B cell receptor (BCR) signaling regulates PRMT5 expression in DLBCL cells. Immunohistochemical analysis reveals elevated levels of PRMT5 expression in DLBCL cases and in germinal center (GC) B cells when compared to naive B cells. PRMT5 can be induced in naive B cells by BCR stimulation. We discovered that BTK-NF-κB signaling induces PRMT5 transcription in activated B cell-like (ABC) DLBCL cells while BCR downstream PI3K-AKT-MYC signaling upregulates PRMT5 expression in both ABC and GCB DLBCL cells. PRMT5 inhibition inhibits the growth of DLBCL cells in vitro and patient derived xenografts. Genomic and biochemical analysis demonstrate that PRMT5 promotes cell cycle progression and activates PI3K-AKT signaling, suggesting a feedback regulatory mechanism to enhance cell survival and proliferation. Co-targeting PRMT5 and AKT by their specific inhibitors is lethal to DLBCL cell lines and primary cancer cells. Therefore, this study provides a mechanistic rationale for clinical trials to evaluate PRMT5 and AKT inhibitors for DLBCL.

Original languageEnglish (US)
Pages (from-to)2898-2911
Number of pages14
JournalLeukemia
Volume33
Issue number12
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Zhu, F., Guo, H., Bates, P. D., Zhang, S., Zhang, H., Nomie, K. J., Li, Y., Lu, L., Seibold, K. R., Wang, F., Rumball, I., Cameron, H., Hoang, N. M., Yang, D. T., Xu, W., Zhang, L., Wang, M., Capitini, C. M., & Rui, L. (2019). PRMT5 is upregulated by B-cell receptor signaling and forms a positive-feedback loop with PI3K/AKT in lymphoma cells. Leukemia, 33(12), 2898-2911. https://doi.org/10.1038/s41375-019-0489-6