TP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma Journal Article
| Authors: | Erazo, T.; Evans, C. M.; Zakheim, D.; Chu, K. L.; Refermat, A. Y.; Asgari, Z.; Yang, X.; Da Silva Ferreira, M.; Mehta, S.; Russo, M. V.; Knezevic, A.; Zhang, X. P.; Chen, Z.; Fennell, M.; Garippa, R.; Seshan, V.; de Stanchina, E.; Barbash, O.; Batlevi, C. L.; Leslie, C. S.; Melnick, A. M.; Younes, A.; Kharas, M. G. |
| Article Title: | TP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma |
| 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. © 2022, The Author(s). |
| Keywords: | adult; controlled study; unclassified drug; gene mutation; human cell; gene deletion; genetics; mutation; drug potentiation; nonhuman; cancer patient; mouse; metabolism; animal tissue; protein bcl 2; apoptosis; enzyme inhibition; gene expression; embryo; protein depletion; animal experiment; animal model; protein; drug resistance; cell line, tumor; protein p53; cancer resistance; rna binding protein; rna-binding proteins; cancer inhibition; b cell lymphoma; lymphoma, b-cell; myc protein; tumor cell line; lymphoma; tumor suppressor protein p53; tp53 protein, human; proto-oncogene proteins c-bcl-2; protein inhibitor; protein arginine methyltransferase; protein arginine methyltransferase 5; cell; molecularly targeted therapy; translation regulation; methyltransferase inhibitor; protein-arginine n-methyltransferases; cell component; humans; human; female; article; venetoclax; crispr-cas9 system; gene knockout; msi2 protein, human; gsk 025; gsk 591; musashi2 protein; ro 08 2750; prmt5 protein, human |
| Journal Title: | Nature Communications |
| Volume: | 13 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-09-27 |
| Start Page: | 5676 |
| Language: | English |
| DOI: | 10.1038/s41467-022-33137-8 |
| PUBMED: | 36167829 |
| PROVIDER: | scopus |
| PMCID: | PMC9515221 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2022 -- Source: Scopus |
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