DNA Damage Responses Coordinate Survival and Cell Death Switching In Lymphocytes

Background
During their development, immune cells must intentionally generate and repair breaks in their DNA in order to assemble the genes necessary for a diverse immune response.  Multiple signals in early immune cells cooperate to ensure that these DNA breaks are properly repaired. Errors in these processes can derail normal development and trigger transformation into leukemia.

Our research studies how immune cells respond to the DNA breaks in order to support correct repair and minimize the chances of deleterious events that could generate malignancies. Recent work has demonstrated that the DNA breaks themselves activate distinct pathways to first support cell survival and then subsequently trigger cell death mechanisms. This temporal sequence of survival and cell death allows time for DNA break repair but triggers elimination of cells with persistent DNA damage, which are at risk for errors that could initiate leukemia formation. How cells coordinate this balanced signaling is unknown. Interestingly, though, these signals are unique to physiologic DNA breaks, those encountered in normal development, as DNA damage from radiation or chemotherapy agents activate alternative pathways that trigger cell death rather than survival.

Project Goal
The goal of this project is to understand how survival and cell death signaling is controlled in response to DNA breaks.  Ultimately, these studies will identify new mechanisms in immune cells that ensure normal maturation and inhibit cancerous transformation. Understanding these processes will provide insights into the development and treatment of leukemia and lymphoma.