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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. 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. [ABSTRACT FROM AUTHOR]