Rapamycin, clinically known as Rapmune or Sirolimus, and its derivatives are widely used clinically for their anti-proliferation effect in treating a wide variety of human diseases including cardiovascular diseases and cancer. It is also commonly used in transplantation due to its immunosuppressive effects. However, recent studies from our group indicate that chronic treatment with rapamycin could lead to augmented DNA damage such as chromosome breaks that are inherently dangerous since it will lead to mutations that are a common cause of blood cancers such as leukemia and lymphoma.

Our laboratory has studied Sin1, a critical molecule required for the function of mTOR, the cellular target of rapamycin. We showed that Sin1 forms a specific complex with mTOR to regulate the B cell receptor-mediated signals that are essential for shutting down the expression of recombination activation gene (Rag) during B cell development. Although Rag genes are absolutely required for generation of mature B lymphocytes, unchecked expression of Rag genes is also a potential risk for developing B cell tumors since it will introduce double-strand DNA breaks, a form of DNA damage that has been associated with many forms of blood cancers like T and B cell leukemia and lymphoma. In our preliminary study, we have revealed a key function of Sin1 in suppressing Rag gene expression in developing B cells. We showed that this Sin1 function is mediated by the mTOR activity. Importantly, we revealed that disruption of mTOR complex 2 by rapamycin treatment also led to an increased Rag gene expression. Our preliminary studies lead us to hypothesize that Sin1 functions through mTORC2, is able to protect the genome stability by minimizing DNA damage caused by excessive Rag gene expression in developing B cells. Alteration of this pathway, either by mutations of the genes in the mTORC2 pathway or by treatment with the anti-tumor drug rapamycin, may increase the risk of B cell leukemia or lymphoma development.

Our proposed research will investigate how the Sin1-mTORC2 pathway is utilized by developing B cells to control Rag gene expression, and we will study how this pathway regulates normal B cell growth and survival. Furthermore, we will determine if blocking this pathway may increase the risk of B cell tumor development. These studies will elucidate how mTOR signaling regulates Rag gene expression and will reveal if disrupting mTOR function may influence the risk of accumulating Rag-mediated DNA damage and tumor formation in B lymphocytes. Completion of the proposed experiments will provide key insights into the mechanism through which mTOR inhibitors such as Sirolimus elicit not only their clinically useful immunosuppressive and antitumor effects but also their detrimental effects in promoting blood cancer formation. Together, these studies will provide a better understanding of the mTORC2 pathway controlled by Sin1 in B cells, and will provide critical clues on how to improve therapeutic usages of the mTOR inhibitors to treat human diseases while limiting their potential risk in causing other diseases such as blood cancers.