Antigen Receptor Gene Assembly and Lymphoid Tumorigenesis:
The adaptive immune system is able to respond to a diverse array of pathogenic infections through specific receptors: T cell receptors (TCR) for T cells and immunoglobulin (Ig or antibody) for B cells. Antigen receptor genes are assembled from component V (variable), D (diversity), and J (joining) gene segments in a process called V(D)J recombination. Because V(D)J recombination involves generation and repair of DNA double strand breaks (DSBs), which can result in cell cycle arrest, genome instability, and tumorigenesis, the process is tightly controlled both before and after DNA cleavage. We have found that transcriptional enhancers and promoters regulate V(D)J recombination by regulating gene segment accessibility as well as stage- and site-specificity. Furthermore, we found that inactivation of transcription enhancers and promoters results in block of lymphocyte development that can cooperate with loss of p53 in lymphomagenesis. For example, introduction of the TCR beta enhancer mutation into p53-deficient mice dramatically accelerates the development of T cell lymphomas. We are investigating molecular mechanisms underlying the observed development of lymphomas in the mutant mice.