Project Summary Diffuse large B cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma and the most common hematologic malignancy. DLBCL exhibits significant molecular and clinical heterogeneity, yet all patients are treated with standard chemoimmunotherapy. As such, there is a strong clinical need to identify biomarkers of drug response and novel therapies to improve patient outcomes. BCL10 mutations are prevalent among DLBCL subtypes and recurrent mutations frequently truncate the BCL10 protein’s regulatory C-terminus. BCL10 is a core component of the CARD11 (CARMA1)-BCL10-MALT1 complex, which activates downstream oncogenic pathways like JNK and NF-kB in DLBCL; however, the mechanisms by which BCL10 mutations promote lymphomagenesis in DLBCL are poorly understood. Recent results implicate BCL10 mutations in the induction of NF-kB signaling and MALT1 protease activity and Bruton’s Tyrosine Kinase inhibitor (BTKi) resistance. The overall objective is to understand the role of BCL10 mutations in DLBCL, to determine mechanisms of drug resistance and to identify alternative treatment strategies for patients with these mutations. The central hypothesis that BCL10 mutations are activating in nature, driving lymphomagenesis and resistance to BTKis, will be tested through the following specific aims: 1) Understand the role of BCL10 mutations in lymphomagenesis using genetically accurate in vivo models, and 2) Identify alternative therapeutic targets to overcome drug resistance mediated by BCL10 mutations. Aim 1 will characterize survival and tumor incidence of a novel murine model generated in the lab containing an inducible BCL10 truncation mutation expressed on the ROSA26 locus of C57BL/6J mice. The model mimics human disease through B-cell-specific activation of BCL10 mutations using Cre-recombination and will also be crossed with mice overexpressing BCL6, which occurs in context with BCL10 mutations. Aim 2 will identify compounds to attack BCL10 mutated cells alone or in combination with BTKis by implementing small molecule synergy screens that target the BCR, NF- kB and parallel signaling pathways. The expected outcome is the creation of genetically accurate in vivo models of BCL10 mutations to understand their lymphomagenic potential, to define BCL10 as a biomarker of BTKi resistance, and to identify novel, targetable dependencies induced by BCL10 mutations. The proposed research is significant because it will uncover mechanisms of lymphomagenesis, identify biomarkers to guide clinical decision-making in DLBCL and discover potential drug targets to overcome resistance or synergize with existing therapies. Also, these studies are innovative because the described mouse model will be the first to characterize BCL10 mutations in vivo and will provide a novel context to study lymphomagenesis and drug resistance driven by BCL10 mutations. Overall, this research will have positive impacts as identifying BCL10 as a biomarker for response to therapy ...