MECHANISMS OF CHEMICAL LYMPHOMAGENESIS

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The goal of this research program is a comprehensive analysis of the mechanisms whereby painting the skin of RF strain mice with the carcinogen, 3-methylcholanthrene (MCA), rapidly induces a near 100 percent incidence of thymic lymphoma. Each project in the program will approach the problem from a unique perspective, using different strategies and different techniques ranging from studies in vivo through work with cultured lymphoma cell lines to molecular studies by recombinant DNA techniques. Cells of primary lymphomas and of lymphoma cell lines will be characterized antigenically and virologically, and their capacity to elicit transplantation immunity and specific cellular immune responses will be determined. The nature of the nonmendelian, maternally transmitted factor of RF mice which suppresses expression of endogenous murine leukemia virus (MuLV) and spontaneous lymphoma will be studied. A recently identified dominant gene which confers resistance to MCA induction of lymphoma--and possibly to x-ray induction of lymphoma, as well--will be studied in order to determine its map location and its mechanism of action. The role of endogenous MuLV in MCA lymphomagenesis will be extensively explored. Cells of RF lymphomas will be examined for new MuLV proviral information present in their chromosomal DNA by comparison with DNA from embryo cells or from normal lymphocytes, and any such new proviruses will be mapped within the cellular genome. Recombinant DNA techniques will be used in the characterization of cytoplasmic RNA transcripts containing viral information will be made in an attempt to identify host genes (candidate cellular oncogenes) and their products that are expressed as a result of genomic rearrangements. A detailed examination of differences in overall gene expression between normal and lymphoma cells will be made. The extent to which findings in the system of MCA-induced RF lymphomas can be generalized to other systems of lymphoma induction in this and other strains of mice will be explored.