SUMMARY Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that is not yet curable. Both as monotherapies and in combination, the Bruton's tyrosine kinase inhibitor ibrutinib and the BH3 mimetic BCL2 inhibitor venetoclax have proven to be effective treatment options for MCL. However, only 21% of patients who received monotherapies ibrutinib or venetoclax and 71% of patients who received the combined therapy achieved a complete response. Furthermore, mono- and dual resistance frequently develops. Therefore, there is an urgent unmet need to overcome resistance to these agents and to study alternative treatment options. Constitutive NF- ?B activation is a hallmark of MCL. Indeed, next generation sequencing analysis of 110 MCL patient samples revealed that genes in the NF-?B signaling pathway had the highest mutation rate (29%), indicating the significant contribution of NF-?B signaling to ibrutinib resistance in MCL. Through whole transcriptomic sequencing, we showed that mucosa-associated lymphoid tissue transformation protein (MALT1) is overexpressed and hyperactive in ibrutinib-resistant and ibrutinib-venetoclax dual-resistant MCL cells. MALT1 is a unique paracaspase within the human genome, and it plays a crucial role in NF-?B signaling, suggesting that MALT1 may be a potential therapeutic target to overcome ibrutinib resistance and ibrutinib-venetoclax dual-resistance without significant off-target side effects. Indeed, MI-2, a MALT1 inhibitor, has been shown to selectively target MALT1 in activated B-cell-like diffuse large B-cell lymphoma and chronic lymphocytic leukemia. Our preliminary data show that MI-2 is highly potent in killing ibrutinib-resistant and ibrutinib-venetoclax dual-resistant MCL cells. To address the underlying mechanisms by which MALT1 contributes to therapeutic resistance and how targeting MALT1 can overcome ibrutinib resistance and ibrutinib-venetoclax dual resistance, we aim to 1) determine the efficacy of MI-2 as a single agent or in combination with other agents in MCL cell lines, primary MCL patient samples, and PDX models in vitro; 2) characterize MALT1-mediated mechanisms underlying MCL disease progression and ibrutinib-venetoclax resistance by introducing MALT1 clinical mutants into MCL cells in vitro; and 3) determine the efficacy of targeting MALT1 alone or with other target(s) to overcome ibrutinib-venetoclax resistance in vivo using MCL PDX mouse models. Successful completion of the proposed study will provide strong evidence demonstrating the role of MALT1 in MCL malignancy and therapeutic resistance and how targeting the unique paracaspase MALT1 may overcome ibrutinib resistance and ibrutinib-venetoclax dual resistance, ultimately leading to clinical strategies to treat ibrutinib and/or venetoclax-refractory/relapsed MCL patients.