This project is based on the hypothesis that mechanisms controlling mature B cell survival also operate in lymphomas originating from these cells. Specifically, we address three survival determinants of normal mature B cells, namely B cell antigen receptor (BCR), BAFF receptor (BAFF-R) and NFicB signaling. Using mouse models of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), we ask whether BCR expression is critical for the survival of the tumor cells. In the case of FL, we also address the question of BCR specificity, and in that of DLBCL, BAFF-R dependency, both of which appear relevant because of suggestive results in the literature on human lymphomas. The long-term goal of these experiments is the identification of potential molecular targets of therapeutic intervention. With respect to NFicB signaling, there is evidence for constitutive activation and vital importance of this pathway in a subset of human DLBCLs, but the mechanisms by which these tumors arise, are unknown. Accordingly, we plan to generate DLBCL-like tumors in the mouse, by combining constitutive """"""""canonical"""""""" NFicB signaling with other oncogenic events known to play a role in the pathogenesis of such lymphomas. We will also study the role of the so-called """"""""alternative"""""""" NFicB signaling pathway in this process, which has received little attention in the study of human lymphomas. Lymphomas arising in the experimental mice will be compared to their human counterparts in terms of gene expression and chromosomal translocations, with the aim of identifying and studying common mechanisms of pathogenesis operating in these tumors. In technical terms, we propose an approach, in which methods of conditional gene targeting serve to introduce targeted mutations and specific genetic switches specifically into GC B cells of the mouse in vivo, or into isolated lymphoma cells in vitro, using the bacteriophage-derived Cre/loxP system. Most of the technical tools required for the experiments are already available, but some technical advances are projected in the proposed work. The relevance of the work for public health comes from the fact that GC-derived lymphomas still represent a major problem in human medicine and that the work may open the way to new therapies and generate animal models of such diseases in which disease pathogenesis and progression can be easily studied.
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