Grant: Joint Canada-Israel Health Research Program

B lymphocytes are a specific type of white blood cell within our immune system. The job of B lymphocytes is to produce and export antibodies which seek out, attach to, and neutralize microbes and toxins. A unique way that B lymphocytes boost their antibody response is through making changes in the genes that encode for antibodies. These genetic changes in B lymphocytes are carried out by activation induced cytidine deaminase (AID), an enzyme that alters the sequence of antibody genes, leading to improved antibodies and hence better immunity. However, AID activity is not perfect and is often misdirected to the wrong genes, or mis-expressed in the wrong cell types. When this happens, AID activity results in genetic mutations that can transform healthy cells into cancers. As a result, AID is now recognized as a leading cause of aggressive lymphoma/leukemia and several solid tissue tumors. Furthermore, continued AID activity in cancer cells increases their ability to mutate and therefore become resistant to therapeutic approaches. Thus, the current scientific dogma is that AID causes mutations to the genome of cells which in turn results in causing and/or exacerbating cancer. We have recently obtained strong preliminary data which hints at the possibility of a completely new aspect of AID activity. We have found that DNA damaged by external sources such as radiation can itself attract AID and that this may serve to correct/repair some of the damage. Here we are proposing to study the extent and mechanisms of this effect, and investigate whether it represents a possible pathway by which cancer cells can evade or become resistant to chemotherapy or radiation therapy since many cancer therapies work through inducing DNA damage. Our results and future studies outlined in this proposal potentially have important implications for cancer treatment strategies.