BAF complex deregulation in lymphoma

PROJECT SUMMARY Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are highly aggressive B-cell malignancies that are commonly treated with chemotherapy plus an anti-CD20 antibody, Rituximab. High-intensity chemotherapy is required in BL patients, which is associated with severe toxicity and treatment-related mortality in 10% of patients. Of the patients able to endure therapy, 36% will suffer disease progression and have a dismal outcome, with only a 1% 3-year progression-free-survival in patients that are primary-refractory. A similar fraction of DLBCL patients progress during/following first-line therapy and have a median overall survival of 6.3 months. Recent genomic studies have identified co-occurring genetic alterations that are highly-recurrent in BL and DLBCL tumors. However, detailed functional analyses have not been performed for the majority of these driver mutations, and hence there are currently no available targeted therapeutic strategies in either disease. Mutations of the SMARCA4 and ARID1A genes are together found in approximately 40% of BL tumors, and 12% of DLBCL tumors. These genes encode two components of a multi-subunit complex, the BAF (aka SWI/SNF) complex, which functions to activate gene expression by “unpacking” closed and silent states to become open and active genes. Mutations of SMARCA4 perturb its activity by affecting the catalytic domain, and mutations of ARID1A lead to loss of protein expression, together representing two alternative mechanisms for loss of function in the BAF complex. Although the function of the BAF complex has been recently described in other malignancies, its function during B-cell development, and therefore the consequence of its inactivation in B-cell lymphoma, remains to be explored. We have developed animal and cell line models of SMARCA4 and ARID1A inactivation and found that they regulate distinct processes in B-cell development. We will leverage these models and cutting-edge genomics approaches to understand both the molecular and immunological consequences of BAF complex deregulation in B-cell lymphoma. By contrasting and comparing the roles of two key components of the BAF complex, SMARCA4 and ARID1A, we hope to gain detailed insight into the role of discrete BAF complexes and their redundant and non-redundant roles. This work will uncover the biology of BL and DLBCL tumors carrying BAF complex mutations, which can lead to advances in precision medicine targeting and therapies for this disease, as well as for other cancers.