The induction of plasmacytomas (PCTs) in the peritoneal cavity of BALB/cAn mice by plastics, paraffin oils or silicone gels is a model system for identifying the steps and stages of neoplastic development. An early oncogenic event in plasmacytomagenesis (PCTGEN) is a chromosomal translocation that illegitimately recombines c-myc with an Ig locus gene resulting in deregulation of c-myc transcription. Recent evidence from a highly sensitive nested PCR detection method indicates this step probably takes place before the introduction of the peritoneal inducing agent. A second consistent tumor suppressor phenotype, i.e., loss of the functional TGF-b receptor TbRII has been identified. Many of the steps in PCTGEN take place in the chronic inflammatory microenvironment of the oil granuloma induced by pristane or silicone gels. PCTGEN can be dramatically inhibited by the chronic administration of the cyclooxygenase inhibitor, indomethacin. This suggests that a prostaglandin produced by an accessory cell is an important effector in plasmacytoma develoment. In vitro studies implicate PGE2 and a cAMP sensitive step as important factors in stimulating IL-6 production. Recent work demonstrating the resistance of BALB/c.CBA/N congenic mice to PCT induction implicates the btk pathway and the ability of B cells in BALB/c mice to respond to auto and environmental (gut flora) antigens in PCTGEN. Much of our current effort focuses on the role of environmental factors in PCTGEN. The presence of the conventional microflora appears to be critical. We characterize the antigen binding activities of myeloma proteins for clues that link the gut flora to B cell clonal longevity. We are studying the role of other environmental factors relating to diet, i.e., fatty acid content, on PCTGEN.
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