: A new direction in determining the role of the TCL1 (T cell leukemia-1) oncogene in B-cell development and neoplasia is highlighted by this application. We found that TCL1 expression is normally extinguished during B-lymphocyte maturation to memory or plasma cells in reactive germinal centers (GC) of lymphoid tissues. However, using subtractive hybridization, we also identified aberrant, high level TCL1 expression in -~8O% of post-GC-derived AIDS diffuse large B-cell lymphoma patient samples. This discovery makes TCL1 the most prevalent oncogene associated with this large subgroup of B-lymphomas and strongly implicates its role in AIDS-lymphomagenesis. The pattern of regulated expression led us to propose a model in which TCL1 primarily functions in cell survival and to a lesser extent in cell proliferation. We further propose that the normal mechanisms that down-regulate TCL1 expression are mainly epigenetic and are disrupted in AIDS, resulting in sustained, high level expression in B-cells. Increased protection and proliferation of B-cells that otherwise would be eliminated or kept quiescent would yield a survival advantage and, over the long-term, allow accumulated mutations to yield aggressive B-cell tumors, as seen in many AIDS patients. Support for this model has now been obtained by our group and by others who have shown an interaction between Tc11 and Akt (protein kinase B). Akt functions as an essential cellular kinase that mainly promotes cell survival. Our approach for testing the hypothesis that dysregulated TCL1 expression alters normal B-cell homeostasis and promotes lymphomas is straightforward. We will determine key features of the epigenetic regulatory mechanisms we believe are controlling TCL1 expression and investigate the biological significance of dysregulation in an animal model system. Accordingly, specific aim 1 studies the epigenetic mechanisms regulating TCL1 gene activity while specific aim II assesses the impact of abnormal regulation in our now established transgenic mouse model. Then, specific aim III determines how TCL1 initiates B-cell transformation by examining the development of autoantibodies and the role of additional mutations from errors in the mechanisms that normally operate in GCs to drive antibody diversity. Because of its strategic position down-stream of PTEN and other known tumor promoting proteins in the Akt activation cascade, these studies also presage future evaluations of TCL1 as a potential diagnostic or therapeutic target molecule.
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