We utilized two recently developed transgenic in vivo mutagenicity assays that are based on the phage lambda-derived shuttle vector, lambdaLIZ, and the plasmid-derived shuttle vector, placZ, to study the role of B-cell mutagenesis in the pathogenesis of inflammation-induced peritoneal plasmacytomas in genetically susceptible BALB/c mice. The studies include (a) the mutagenicity of the inflammatory granuloma, which is the tissue site where plasmacytomas develop, (b) the genetic control of B-cell mutagenesis and its association with the genetic susceptibility/resistance to plasma cell tumor development, and (c) the presumed requirement of B-cell mutagenesis for plasmacytoma development. To devise an experimental system that is conducive for mouse plasmacytoma research, Kevin Kelliher decided to backcross the above-mentioned shuttle vectors onto plasmacytoma-susceptible BALB/cAnPt mice and plasmacytoma-resistant DBA/2N mice. He has obtained genetically pure, congenic BALB/cAnPt.lambdaLIZ and DBA/2N.lambdaLIZ mice; the backcross of the transgene, placZ, is near completion.While the backcross protocol was still ongoing, Klaus Felix was already able to demonstrated the great potential of the lambdaLIZ-based transgenic mutagenesis assay for determining mutant frequencies in B cells. He has studied the mutagenicity of small organosilicone compounds (siloxanes) known to leak from silicone gels that were used to induce plasmacytomas in BALB/c mice (Carcinogenesis 19,315-320, 1998). Furthermore, he devised a co-incubation system in which splenic B lymphoblasts harboring lambdaLIZ were exposed to phagocytes undergoing an oxidative burst. Mutant frequencies in B cells were found to be 6-fold increased (Eur. J. Immunol. 27, 2160-2164, 1997). Most recently, Klaus Felix found that the mean mutant rates in the spleen of mice exposed to sustained oxidative stress were approximately 3-fold increased in plasmacytoma-susceptible BALB/cAnPt.lambdaLIZ N5 mice, but not in plasmacytoma-resistant DBA/2N.lambdaLIZ N5 mice. This finding suggested a correlation between the genetic susceptibility to inflammation-induced peritoneal plasmacytomagenesis and the phenotype of increased mutagenesis in lymphoid tissues (Cancer Res. 58, 1616-1619, 1998).
| Kovalchuk, A L; Qi, C F; Torrey, T A et al. (2000) Burkitt lymphoma in the mouse. J Exp Med 192:1183-90 |
