A number of lymphoma including follicular cell, Burkitt's, and diffuse large cell lymphoma are known to originate from lymphoid tissues. Although the pathobiology of malignant B cells has been studied extensively, the role of the germinal center (GC)-microenvironment in lymphomagenesis has not been investigated in the molecular term. The GC is an unique microenvironment where antigen-activated B cells undergo clonal selection by proliferation and apoptosis, selecting memory B cells. At the same time, the genetic events such as somatic mutation and Ig-isotype switching occur, producing high-affinity antibodies. B cell lymphoma originate as a consequence of the genetic mobility and mutability. Follicular dendritic cell (FDC) is a stromal cell located inside but not outside of the GC. Furthermore, most of the GC-B cells die by apoptosis unless rescued by FDC. FDC provides the signals for survival and proliferation of GC-B cells and lymphoma cells in the early stage of lymphomagenesis. The objective is to characterize the function of FDC in B cell lymphomagenesis in the molecular term.
Specific Aims are to identify the FDC-signaling molecules, using the FDC-specific monoclonal antibodies and a mammalian cell expression vector, and to characterize the function of the FDC-molecules in lymphomagenesis in vivo. The molecular identification of the FDC signaling molecule will help us understand the unique role of the stromal cells in blast transformation of lymphoma cells. In addition, it will facilitate the development of the therapeutic monoclonal antibodies and antagonists which block the propagation of lymphoma cells. Furthermore, our in vivo experimental model will be useful in discovering the target genes for the anti-cancer drugs.
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