TP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma.
Tatiana ErazoChiara M EvansDaniel ZakheimKaren L ChuAlice Yunsi RefermatZahra AsgariXuejing YangMariana Da Silva FerreiraSanjoy MehtaMarco Vincenzo RussoAndrea KnezevicXi-Ping ZhangZhengming ChenMyles FennellRalph GarippaVenkatraman E SeshanElisa de StanchinaOlena BarbashConnie Lee BatleviChristina S LeslieAri M MelnickAnas YounesMichael Gregory KharasPublished in: Nature communications (2022)
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 TP53 R248W 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.
Keyphrases
- binding protein
- cell cycle
- gene expression
- genome wide
- crispr cas
- diffuse large b cell lymphoma
- poor prognosis
- dna methylation
- signaling pathway
- cell proliferation
- end stage renal disease
- pi k akt
- chronic kidney disease
- newly diagnosed
- nitric oxide
- ejection fraction
- cell death
- prognostic factors
- high throughput
- single cell
- long non coding rna
- combination therapy
- replacement therapy