Nature Communications (Sep 2022)
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,
- Karen L. Chu,
- Alice Yunsi Refermat,
- Zahra Asgari,
- Xuejing Yang,
- Mariana Da Silva Ferreira,
- Sanjoy Mehta,
- Marco Vincenzo Russo,
- Andrea Knezevic,
- Xi-Ping Zhang,
- Zhengming Chen,
- Myles Fennell,
- Ralph Garippa,
- Venkatraman Seshan,
- Elisa de Stanchina,
- Olena Barbash,
- Connie Lee Batlevi,
- Christina S. Leslie,
- Ari M. Melnick,
- Anas Younes,
- Michael G. Kharas
Affiliations
- Tatiana Erazo
- Molecular Pharmacology Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center
- Chiara M. Evans
- Molecular Pharmacology Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center
- Daniel Zakheim
- Gene Editing and Screening Core, Memorial Sloan Kettering Cancer Center
- Karen L. Chu
- Molecular Pharmacology Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center
- Alice Yunsi Refermat
- Gene Editing and Screening Core, Memorial Sloan Kettering Cancer Center
- Zahra Asgari
- Lymphoma Service, Memorial Sloan Kettering Cancer Center
- Xuejing Yang
- Molecular Pharmacology Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center
- Mariana Da Silva Ferreira
- Molecular Pharmacology Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center
- Sanjoy Mehta
- Gene Editing and Screening Core, Memorial Sloan Kettering Cancer Center
- Marco Vincenzo Russo
- Gene Editing and Screening Core, Memorial Sloan Kettering Cancer Center
- Andrea Knezevic
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center
- Xi-Ping Zhang
- Epigenetics Research Unit, GlaxoSmithKline
- Zhengming Chen
- Division of Biostatistics and Epidemiology, Weill Cornell Medicine
- Myles Fennell
- Gene Editing and Screening Core, Memorial Sloan Kettering Cancer Center
- Ralph Garippa
- Gene Editing and Screening Core, Memorial Sloan Kettering Cancer Center
- Venkatraman Seshan
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center
- Elisa de Stanchina
- Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center
- Olena Barbash
- Epigenetics Research Unit, GlaxoSmithKline
- Connie Lee Batlevi
- Lymphoma Service, Memorial Sloan Kettering Cancer Center
- Christina S. Leslie
- Computational Biology Program, Memorial Sloan Kettering Cancer Center
- Ari M. Melnick
- Division of Hematology and Medical Oncology, Sanford I. Weill Department of Medicine, Weill Cornell Medicine
- Anas Younes
- Lymphoma Service, Memorial Sloan Kettering Cancer Center
- Michael G. Kharas
- Molecular Pharmacology Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center
- DOI
- https://doi.org/10.1038/s41467-022-33137-8
- Journal volume & issue
-
Vol. 13,
no. 1
pp. 1 – 18
Abstract
Inhibition of the protein arginine methyltransferase PRMT5 has been suggested as a promising therapy for lymphoma. Here, the authors show that TP53 loss of function and MUSASHI-2 (MSI2) expression are biomarkers of resistance to PRMT5-targeted therapy in B-cell lymphoma. Moreover, combining PRMT5 inhibition with MSI2 or BCL-2 inhibitors blocks the translation of key drivers of lymphoma, c-MYC and BCL-2, inhibiting cell growth.
