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

• Published in: Nature communications Vol. 14; no. 1; p. 97
• Main Authors: Hing, Zachary A., Walker, Janek S., Whipp, Ethan C., Brinton, Lindsey, Cannon, Matthew, Zhang, Pu, Sher, Steven, 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., Ozer, Gulcin H., Yilmaz, Selen A., Harrington, Bonnie K., Lehman, Amy M., Yu, Lianbo, Coppola, Vincenzo, Yan, Pearlly, Scherle, Peggy, Wang, Min, Pitis, Philip, Xu, Chaoyi, Vaddi, Kris, Chen-Kiang, Selina, Woyach, Jennifer, Blachly, James S., Alinari, Lapo, Yang, Yiping, Byrd, John C., Baiocchi, Robert A., Blaser, Bradley W., Lapalombella, Rosa
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.01.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/105; 38; 38/39; 38/91; 49; 49/31; 631/67/1990/283/1895; 631/67/1990/291/1621/1915; 631/67/70; 64/110; 64/60; Animals; B-cell lymphoma; Chronic lymphocytic leukemia; Genetic transformation; Humanities and Social Sciences; Inhibitors; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lymphocytes B; Lymphoma; Lymphoma, Large B-Cell, Diffuse - pathology; Mice; multidisciplinary; Protein arginine methyltransferase; Risk; Science; Science (multidisciplinary); Selectivity; Transformations; Transgenic mice; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35778-1

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. Richter’s Transformation is a treatment-resistant and fatal progression from Chronic Lymphocytic Leukemia (CLL) to an aggressive lymphoma. Here, the authors show that PRMT5 is upregulated months prior to and after transformation, PRMT5 overexpression in a CLL mouse model leads to increased risk of transformation, and that targeted PRMT5 inhibition prolongs survival and delays disease development.