The major project in the laboratory is to determine the pathogenetic mechanisms involved in the development of parrafin oil (pristane) induced plasmacytomas in BALB/c mice. BALB/cAn mice are highly susceptible to developing these tumors while most other strains are resistant. Over 95% of plasmacytomas induced by pristane have chromosomal translocations (rcpt (12;15), rcpt (6:15)) involving directly or indirectly the c-myc locus on chr 15.
One aim of our work is to identify the origin of mutagenic substances associated with the chronic inflammatory tissue evoked by pristane. We hypothesize these are oxygen and lipid radicals generated by inflammatory cells. A major clue in this work is provided by the finding that indomethacin inhibits plasmacytoma formation. Studies are aimed at determining the mode of action of indomethacin. We have developed model genetic systems for finding the genetic basis of susceptibility and resistance to plasmacytoma development by using BALB/cAn.DBA/2 (C.D2) and BALB/cAn.BALB/cJ (C.J) congenics. Several genes have been identified that confer partial resistance. Congenic mice constructed by combining two weakly active resistance genes have produced even stronger resistance. In collaboration with Dr. K. Sanford, we are studying genes associated with DNA repair deficiencies in BALB/cAn mice and C.D2 and C.J congenics. We have identified two genes in DBA/2. Plasmacytomas can be introduced with short latent periods in BALB/cAn mice by the infection of pristane conditioned mice with retroviruses containing oncogenes. Our recent studies demonstrate the potent cooperative action of myc and ras (in collaboration with K. Marcu, Stony Brook).
