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Lymphoma

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

Leukemia volume 33, pages 2898–2911 (2019)Cite this article

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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.

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Acknowledgements

We thank Dr. Scott McMurray for providing tonsils, Dr. Sameer Mathur for providing PBMCs, and Dr. Stephen Nimer for providing PRMT5 plasmid. This work was supported by the National Institutes of Health/National Cancer Institute (NIH/NCI) grant R01 CA187299 (LR), UW-Madison Forward Lymphoma Fund (LL), NIH/NCI grant K08 CA174750 and the MACC fund (CMC). This work was also supported in part by NIH/NCI P30 CA014520—UW Comprehensive Cancer Center Support.

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Authors and Affiliations

  1. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53792, USA

    Fen Zhu, Yangguang Li, Li Lu, Fangyu Wang, Ian Rumball, Hunter Cameron, Nguyet M. Hoang & Lixin Rui

  2. Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53792, USA

    Fen Zhu, Yangguang Li, Li Lu, Nguyet M. Hoang, David T. Yang, Christian M. Capitini & Lixin Rui

  3. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Hui Guo, Hui Zhang, Krystle J. Nomie, Liang Zhang & Michael Wang

  4. Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53792, USA

    Paul D. Bates, Kaitlyn R. Seibold & Christian M. Capitini

  5. Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN, 46202, USA

    Shanxiang Zhang

  6. Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53792, USA

    David T. Yang

  7. McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI, 53792, USA

    Wei Xu

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  1. Fen Zhu
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Contributions

LR conceived and designed the study, and supervised the research. CMC established the xenograft models, supervised the research and revised the paper. MW and LZ established a PDX model and supervised research on primary cancer cells. FZ, PB, HG, HZ, KJN, SZ, YL, LL, KS, FW, IR, NMH, DTY, and HC performed the research and analyzed the data. WX provided intellectual input in the study design. FZ and LR drafted and revised the paper.

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Correspondence to Michael Wang, Christian M. Capitini or Lixin Rui.

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Zhu, F., Guo, H., Bates, P.D. et al. PRMT5 is upregulated by B-cell receptor signaling and forms a positive-feedback loop with PI3K/AKT in lymphoma cells. Leukemia 33, 2898–2911 (2019). https://doi.org/10.1038/s41375-019-0489-6

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