The overall objective of the research proposed in this grant application is to understand how the absence of E2A results in the development of T cell lymphomas. The E2A proteins are helix-loop-helix proteins, which in thymocytes form heterodimers with HEB, another HLH protein. Recently, we showed that E2A proteins are essential for many aspects of thymocyte differentiation, including V(D)J rearrangement in gammadelta T cells, early alphabeta T cell maturation and positive selection during later stages of T lineage development. Our recent observations indicate that E2A proteins also play a role in apoptotic pathways that are utilized during thymocyte selection. Additionally, we and others as well, have documented that the absence of E2A proteins leads to the rapid development of highly malignant T cell lymphomas. The lymphomas are monoclonal and highly malignant. Furthermore, preliminary data indicates that ectopic expression of E47 in E2A deficient lymphomas blocks cell growth and initiates apoptosis. We propose to continue these studies. How E2A and HEB contribute to thymocyte cell death would be examined. We would examine whether the physiological function of these proteins during thymocyte development is to regulate negative selection. The individual roles of E12, E47 and HEB as potential tumor suppressors will be studied. It is planned to identify down-stream target genes of the E2A gene products and examine their role in lymphomagenesis. Finally, we would examine the role of E2A and HEB in the development of human T acute lymphoblastoid leukemia.
