The major project in the laboratory is to determine pathogenetic mechanisms involved in the development of paraffin 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 translocation [rcpt(12;15), rcpt(6;15)] involving directly or indirectly the c-myc locus on Chr 15. The specific problems on which we are working are: 1) to locate and characterize genes that determine resistance and susceptibility to plasmacytoma induction by peritoneal irritants such as pristane, 2) define environmental factors (antigens, diet, infections) that affect the rate of plasmacytoma formation, and 3) to identify critical mutations that cooperate with c-myc dysregulation in the neoplastic transformation of plasma cells. Substantial progress has now been made with finding plasmacytoma resistance genes of DBA/2 origin. Using a series of BALB/c. DBA/2 congenic strains two genes on Chr 4 have been localized by linkage to Pnd and Lgm-1 that determine partial resistance to plasmacytoma induction by pristane. The functions of these genes are not known, but phenotypically they inhibit the formation and progression of pre-neoplastic plasmacytic foci and plasmacytomas. This phenotype can be detected at day 150 by use of a focus enumeration assay. We are searching for other correlative phenotypes using various DNA repair assays. The progressive isolation of our mouse colony has been associated with a decrease in the incidence of pristane induced plasmacytomas. We have found that immunization with heterologous red blood cells restores the incidence to the 60% level that prevailed 10 years ago when the colony was not so clean. In collaborative studies with K. Marcu we are studying the plasmacytomagenic properties of transforming retroviruses that contain Ha- Ras + p53, IL-6, BCL-2 or E1a. All of these viruses rapidly induce plasmacytomas, but the effectiveness is quite variable.
