Pediatric Burkitt lymphoma (pBL) is the most frequent pediatric lymphoma and has a median onset of 10 years old. Although a large fraction of patients can be cured with high-dose combination chemotherapy, long-term survivors often suffer from treatment-associated morbidity and those that relapse have dismal outcomes.

This highlights a need for better understanding of disease mechanisms so that we can design more effective and less toxic therapies. The cell of origin for pBL arises from B-cells that are undergoing a natural process of proliferation and mutation in response to an antigen, within a microphysiological structure called the germinal center (GC). Under normal circumstances, develo...

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Pediatric Burkitt lymphoma (pBL) is the most frequent pediatric lymphoma and has a median onset of 10 years old. Although a large fraction of patients can be cured with high-dose combination chemotherapy, long-term survivors often suffer from treatment-associated morbidity and those that relapse have dismal outcomes.

This highlights a need for better understanding of disease mechanisms so that we can design more effective and less toxic therapies. The cell of origin for pBL arises from B-cells that are undergoing a natural process of proliferation and mutation in response to an antigen, within a microphysiological structure called the germinal center (GC). Under normal circumstances, development through the GC results in B-cells that can fight infection through the production of antibodies. However, these cells are prone to malignant transformation because they already carry some of the hallmarks of cancer such as rapid proliferation. Mutations that change the way that B-cells develop within the GC can therefore result in lymphoma.

In this study, we will examine the effects of mutations in the SMARCA4 gene, which occur in ~34% of pBL tumors. We will investigate the role of SMARCA4 in regulating normal development of B-cells in the GC, how SMARCA4 regulates the activation of genes that are important cell state transitions and GC exit, and how mutation of SMARCA4 can render cells vulnerable to precision medicine approaches with targeted inhibitors. We anticipate that this will result in a more in-depth understanding of how pBL develops and progresses, and how we may be able to leverage this information towards rationally-targeted therapeutic strategies to improve patient outcomes.

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