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Dysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter’s transformation

Author

Listed:
  • Zachary A. Hing

    (The Ohio State University)

  • Janek S. Walker

    (The Ohio State University)

  • Ethan C. Whipp

    (The Ohio State University)

  • Lindsey Brinton

    (The Ohio State University)

  • Matthew Cannon

    (The Ohio State University)

  • Pu Zhang

    (The Ohio State University)

  • Steven Sher

    (The Ohio State University)

  • Casey B. Cempre

    (The Ohio State University)

  • Fiona Brown

    (The Ohio State University)

  • Porsha L. Smith

    (The Ohio State University)

  • Claudio Agostinelli

    (Haematopathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna)

  • Stefano A. Pileri

    (European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
    University of Bologna)

  • Jordan N. Skinner

    (The Ohio State University)

  • Katie Williams

    (The Ohio State University)

  • Hannah Phillips

    (The Ohio State University)

  • Jami Shaffer

    (The Ohio State University)

  • Larry P. Beaver

    (The Ohio State University)

  • Alexander Pan

    (The Ohio State University)

  • Kyle Shin

    (The Ohio State University)

  • Charles T. Gregory

    (The Ohio State University)

  • Gulcin H. Ozer

    (The Ohio State University)

  • Selen A. Yilmaz

    (The Ohio State University)

  • Bonnie K. Harrington

    (The Ohio State University
    The Ohio State University
    Michigan State University)

  • Amy M. Lehman

    (The Ohio State University)

  • Lianbo Yu

    (The Ohio State University)

  • Vincenzo Coppola

    (The Ohio State University)

  • Pearlly Yan

    (The Ohio State University)

  • Peggy Scherle

    (Prelude Therapeutics)

  • Min Wang

    (Prelude Therapeutics)

  • Philip Pitis

    (Prelude Therapeutics)

  • Chaoyi Xu

    (Prelude Therapeutics)

  • Kris Vaddi

    (Prelude Therapeutics)

  • Selina Chen-Kiang

    (Weill Cornell Medicine)

  • Jennifer Woyach

    (The Ohio State University)

  • James S. Blachly

    (The Ohio State University)

  • Lapo Alinari

    (The Ohio State University)

  • Yiping Yang

    (The Ohio State University)

  • John C. Byrd

    (The Ohio State University
    University of Cincinnati)

  • Robert A. Baiocchi

    (The Ohio State University)

  • Bradley W. Blaser

    (The Ohio State University)

  • Rosa Lapalombella

    (The Ohio State University)

Abstract

Richter’s Transformation (RT) is a poorly understood and fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. Protein arginine methyltransferase 5 (PRMT5) is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 develop a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice develop a highly aggressive disease with transformation that histologically resembles RT; where large-scale transcriptional profiling identifies oncogenic pathways mediating PRMT5-driven disease progression. Lastly, we report the development of a SAM-competitive PRMT5 inhibitor, PRT382, with exclusive selectivity and optimal in vitro and in vivo activity compared to available PRMT5 inhibitors. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases.

Suggested Citation

  • Zachary A. Hing & Janek S. Walker & Ethan C. Whipp & Lindsey Brinton & Matthew Cannon & Pu Zhang & Steven Sher & Casey B. Cempre & Fiona Brown & Porsha L. Smith & Claudio Agostinelli & Stefano A. Pile, 2023. "Dysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter’s transformation," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35778-1
    DOI: 10.1038/s41467-022-35778-1
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    References listed on IDEAS

    as
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