TP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma

Tatiana Erazo, Chiara M. Evans, Daniel Zakheim, Eren L. Chu, Alice Yunsi Refermat, Zahra Asgari, Xuejing Yang, Mariana Silva Ferreira, Sanjoy Mehta, Marco Vincenzo Russo, Andrea Knezevic, Xi-Ping Zhang, Zhengming Chen, Myles Fennell, Ralph Garippa, Venkatraman Seshan, Elisa Stanchina, Olena Barbash, Connie Lee Batlevi, Christina S. Leslie, Ari M. Melnick, Anas Younes () and Michael G. Kharas ()
Additional contact information
Tatiana Erazo: Memorial Sloan Kettering Cancer Center
Chiara M. Evans: Memorial Sloan Kettering Cancer Center
Daniel Zakheim: Memorial Sloan Kettering Cancer Center
Eren L. Chu: Memorial Sloan Kettering Cancer Center
Alice Yunsi Refermat: Memorial Sloan Kettering Cancer Center
Zahra Asgari: Lymphoma Service, Memorial Sloan Kettering Cancer Center
Xuejing Yang: Memorial Sloan Kettering Cancer Center
Mariana Silva Ferreira: Memorial Sloan Kettering Cancer Center
Sanjoy Mehta: Memorial Sloan Kettering Cancer Center
Marco Vincenzo Russo: Memorial Sloan Kettering Cancer Center
Andrea Knezevic: Memorial Sloan Kettering Cancer Center
Xi-Ping Zhang: GlaxoSmithKline
Zhengming Chen: Weill Cornell Medicine
Myles Fennell: Memorial Sloan Kettering Cancer Center
Ralph Garippa: Memorial Sloan Kettering Cancer Center
Venkatraman Seshan: Memorial Sloan Kettering Cancer Center
Elisa Stanchina: Memorial Sloan Kettering Cancer Center
Olena Barbash: GlaxoSmithKline
Connie Lee Batlevi: Lymphoma Service, Memorial Sloan Kettering Cancer Center
Christina S. Leslie: Memorial Sloan Kettering Cancer Center
Ari M. Melnick: Weill Cornell Medicine
Anas Younes: Lymphoma Service, Memorial Sloan Kettering Cancer Center
Michael G. Kharas: Memorial Sloan Kettering Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract To identify drivers of sensitivity and resistance to Protein Arginine Methyltransferase 5 (PRMT5) inhibition, we perform a genome-wide CRISPR/Cas9 screen. We identify TP53 and RNA-binding protein MUSASHI2 (MSI2) as the top-ranked sensitizer and driver of resistance to specific PRMT5i, GSK-591, respectively. TP53 deletion and TP53R248W mutation are biomarkers of resistance to GSK-591. PRMT5 expression correlates with MSI2 expression in lymphoma patients. MSI2 depletion and pharmacological inhibition using Ro 08-2750 (Ro) both synergize with GSK-591 to reduce cell growth. Ro reduces MSI2 binding to its global targets and dual treatment of Ro and PRMT5 inhibitors result in synergistic gene expression changes including cell cycle, P53 and MYC signatures. Dual MSI2 and PRMT5 inhibition further blocks c-MYC and BCL-2 translation. BCL-2 depletion or inhibition with venetoclax synergizes with a PRMT5 inhibitor by inducing reduced cell growth and apoptosis. Thus, we propose a therapeutic strategy in lymphoma that combines PRMT5 with MSI2 or BCL-2 inhibition.

Date: 2022
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DOI: 10.1038/s41467-022-33137-8

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