2. Academic Validation
  3. Dysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter's transformation

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

  • Nat Commun. 2023 Jan 6;14(1):97. doi: 10.1038/s41467-022-35778-1.
Zachary A Hing # 1,  Janek S Walker # 1,  Ethan C Whipp # 1,  Lindsey Brinton 1,  Matthew Cannon 1,  Pu Zhang 1,  Steven Sher 1,  Casey B Cempre 1,  Fiona Brown 1,  Porsha L Smith 1,  Claudio Agostinelli 2,  Stefano A Pileri 3 4,  Jordan N Skinner 1,  Katie Williams 1,  Hannah Phillips 1,  Jami Shaffer 1,  Larry P Beaver 1,  Alexander Pan 1,  Kyle Shin 1,  Charles T Gregory 1,  Gulcin H Ozer 5,  Selen A Yilmaz 5,  Bonnie K Harrington 1 6 7,  Amy M Lehman 8,  Lianbo Yu 8,  Vincenzo Coppola 9,  Pearlly Yan 1,  Peggy Scherle 10,  Min Wang 10,  Philip Pitis 10,  Chaoyi Xu 10,  Kris Vaddi 10,  Selina Chen-Kiang 11,  Jennifer Woyach 1,  James S Blachly 1,  Lapo Alinari 1,  Yiping Yang 1,  John C Byrd 1 12,  Robert A Baiocchi 1,  Bradley W Blaser # 1,  Rosa Lapalombella # 13
Affiliations

Affiliations

  • 1 Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • 2 Haematopathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
  • 3 European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.
  • 4 Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy.
  • 5 Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA.
  • 6 Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA.
  • 7 Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA.
  • 8 Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
  • 9 Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
  • 10 Prelude Therapeutics, Wilmington, DE, USA.
  • 11 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
  • 12 Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA.
  • 13 Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA. rosa.lapalombella@osumc.edu.
  • # Contributed equally.
PMID: 36609611 DOI: 10.1038/s41467-022-35778-1
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.

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