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.