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

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. Pileri, Jordan N. Skinner, Katie Williams, Hannah Phillips, Jami Shaffer, Larry P. Beaver, Alexander Pan, Kyle Shin, Charles T. Gregory, Gulcin H. Ozer, Selen A. Yilmaz, Bonnie K. Harrington, Amy M. Lehman, Lianbo Yu, Vincenzo Coppola, Pearlly Yan, Peggy Scherle, Min Wang, Philip Pitis, Chaoyi Xu, Kris Vaddi, Selina Chen-Kiang, Jennifer Woyach, James S. Blachly, Lapo Alinari, Yiping Yang, John C. Byrd, Robert A. Baiocchi, Bradley W. Blaser and Rosa Lapalombella ()
Additional contact information
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)
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
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
Robert A. Baiocchi: The Ohio State University
Bradley W. Blaser: The Ohio State University
Rosa Lapalombella: The Ohio State University

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-022-35778-1

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