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

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.

 

Comments:

Your proposed therapeutic strategy in lymphoma, combining Protein Arginine Methyltransferase 5 (PRMT5) inhibition with MSI2 or BCL-2 inhibition, appears to be based on a series of findings from a genome-wide CRISPR/Cas9 screen. In this screen, TP53 and the RNA-binding protein MUSASHI2 (MSI2) were identified as the top-ranked sensitizer and driver of resistance, respectively, to a specific PRMT5 inhibitor called GSK-591. It was observed that TP53 deletion and TP53R248W mutation serve as biomarkers for resistance to GSK-591.

Additionally, the expression of PRMT5 was found to correlate with MSI2 expression in lymphoma patients. Further investigations demonstrated that MSI2 depletion and pharmacological inhibition using Ro 08-2750 (Ro) both synergize with GSK-591, resulting in reduced cell growth. Ro treatment was observed to reduce MSI2 binding to its global targets.

Furthermore, the combination of Ro and PRMT5 inhibitors led to synergistic gene expression changes, including alterations in cell cycle, P53, and MYC signatures. The dual inhibition of MSI2 and PRMT5 was found to block c-MYC and BCL-2 translation. Importantly, depletion or inhibition of BCL-2 using venetoclax, in combination with a PRMT5 inhibitor, synergistically induced reduced cell growth and apoptosis.

Based on these findings, you propose a therapeutic strategy for lymphoma that combines PRMT5 inhibition with MSI2 or BCL-2 inhibition. This strategy aims to exploit the synergistic effects observed between PRMT5 inhibitors and inhibitors targeting either MSI2 or BCL-2, potentially leading to enhanced therapeutic efficacy in treating lymphoma.

It's important to note that while the findings you presented are based on scientific research, they may not have undergone extensive clinical validation. Therefore, further studies and clinical trials would be necessary to determine the safety and efficacy of this proposed therapeutic approach in lymphoma treatment.

Related Products

Cat.No. Product Name Information
S8111 GSK591 GSK591 (EPZ015866, GSK3203591) is a potent selective inhibitor of the arginine methyltransferase PRMT5 with IC50 of 4 nM.

Related Targets

PRMT Histone Methyltransferase