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Background:Complex genetic, epigenetic alterations and metabolic reprogramming are among the hallmarks of mantle cell lymphoma, an aggressive B-cell type of non-Hodgkin's lymphoma. CDKN2Aand MTAPare frequently co-deleted in human cancers including MCL. Deletion of MTAPgene results in the accumulation of methylthioadenosine (MTA), a selective inhibitor of protein arginine methyltransferase 5 (PRMT5), signifying a dependence of MTAPdeleted tumors on PRMT5. PRMT5 plays an important role in normal cellular processes viaepigenetic and post-translational modification of RNA splicing, DNA repair and cell cycle regulators. These pathways may be activated in response to targeted therapies to maintain tumor growth and survive chemotherapy. Sustained PRMT5 expression and activity could be therapeutically targeted in MTAP-deficient MCL. Mutations in RNA splicing factors are common in lymphoma and increase the susceptibility to perturbations in splicing events. Deregulated PRMT5 might induce alternative splicing, leading to loss of expression of proteins or epitopes, and subsequent immune evasion and failure of tumor specific immune therapy. Multiple mechanisms may co-exist.