Three questions on plasma cell tumor development are: 1)in which cell in the B cell developmental lineage is the tumor process intiated ?; 2) an Ig/C-Myc chromosomal translocation (CT)is probably the initiating mutation, in what B lineage cell does this occur?; 3. can either processes 1 and 2 be prevented? Understanding B cell development is complicated by the several developmental pathways that precede final maturation to the terminal plasma cell stages including : first differentiation of a fetal (CD5+) B cell that appears to function with germline L and H chain sequences; second the peripheral B cells that separate into extra-follicular and follicular subdivisions. Plasma cell maturation or memory cell formation can take place in the different branches depending upon tissue and environmental conditions. Identifying the clonogenic founder of plasma cell tumor is important for understanding pathogenesis and therapy. In the mouse there are 2 general high incidence models of plasma cell tumor development (PCT) that are potentially useful in defining the clonal origin of the PCTs: first is the induced PCT development by chronic peritoneal inflammation and second is 'spontaneous' PCT formation in the lymphoid tissues of IL-6 transgenic mice. Markers for the initiation of the PCT in both models are the t(12;15) and t(6;15) Ig/C-myc chromosomal translocations (CTs) that occur in over 95% of all tumors. In the 2 model systems the principle mechanism for generating the CTs is AID (Activation Induced Cytidine Deaminase) an enzyme essential for class switch recombination and somatic hypermutation. We have recently been able to induce PCTs in pristane treated Aicda-/-, Bcl-xL(transgenic ) mice and found that these PCTs also harbor Ig/Myc CTs that utilize different mechanisms for illegitimately recombining Ig genes and C-Myc that do not involve AID. This indicates an important physical association of Ig and Myc genes is required for CT initiation and that the critical double stranded DNA breaks are generated independently of RAG1/2 and AID enzymes. The appearance of atypical plasma cells in the medullary cords of IL-6 transgenic mice and the pristane induced oil granuloma has been found to be an early event in PCT development. Using FISH in paraffin tissue sections we are attempting to show a correlation of atypia and Ig/Myc CT development. The high predictable incidence of PCTs in the induced model permits searching for inhibitors of tumor development. The NSAID indomethacin has been shown to a powerful inhibitor of PCT development we are currently exploring two other potential inhibitors: Tempol, a free radical inhibitor (in collaboration with Jim Mitchell)and polyIC an interferon gamma inducer (in collaboration with Sam Baron).
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