Dysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter’s transformation
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Published:2023-01-06
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Hing Zachary A., Walker Janek S.ORCID, Whipp Ethan C.ORCID, Brinton Lindsey, Cannon Matthew, Zhang Pu, Sher StevenORCID, Cempre Casey B., Brown Fiona, Smith Porsha L., Agostinelli Claudio, Pileri Stefano A., Skinner Jordan N., Williams Katie, Phillips Hannah, Shaffer Jami, Beaver Larry P., Pan Alexander, Shin Kyle, Gregory Charles T.ORCID, Ozer Gulcin H., Yilmaz Selen A., Harrington Bonnie K., Lehman Amy M., Yu Lianbo, Coppola VincenzoORCID, Yan PearllyORCID, Scherle Peggy, Wang Min, Pitis Philip, Xu Chaoyi, Vaddi Kris, Chen-Kiang Selina, Woyach JenniferORCID, Blachly James S.ORCID, Alinari Lapo, Yang Yiping, Byrd John C., Baiocchi Robert A., Blaser Bradley W.ORCID, Lapalombella RosaORCID
Abstract
AbstractRichter’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.
Funder
U.S. Department of Health & Human Services | NIH | National Cancer Institute
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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