Malignant transformation is regarded as a multistage process in which genetic alterations are integral events at one or more steps in the multistage pathway leading to tumor development. N-methyl-N-nitrosourea (MNU) is a potent carcinogen that is thought to mediate its effect through alkylating DNA. A single injection of MNU induces thymic lymphoma development in several mouse strains via multiple events (hits). AKR mice are a high lymphoma incidence strain that develop spontaneous thymic lymphoma at 10-12 months of age. Fewer hits are required for MNU induced lymphoma in the AKR strain indicating that AKR mice possess a dominant gene making them more suseptible to lymphoma development. In AKR mice a genetic recombination event between endogenous murine leukemia proviral loci results in recombinant murine leukemia viruses (MLV) that are thought to be the proximal cause of disease. It has been suggested that activation and/or rearrangement of endogenous MLV proviral loci also contribute to chemically induced lymphomagenesis. However, this is a controversial issue and it is difficult to compare the mechanisms involved in chemical vs. viral induced lymphomagenesis in different mouse strains since multiple genetic loci contribute to the host's suseptibility and response to disease. This project is directed towards determining the significance of MLV related cell surface antigens and genetic rearrangements as causative factors leading to lymphomagenesis induced by MNU treatment of young AKR mice. This objective will be accomplished by investigating cellular, molecular and genetic events taht occur during MNU induced lymphomagenesis in young AKR mice. The expression of cell surface differentiation and viral antigens on preleukemic and lymphoma cells will be determined by immunofluouescence and immunochemical techniques. Genetic rearrangements of MLV related genes and selected cellular oncogenes will be evaluated using southern blotting and restriction mapping techniques on lymphoma DNA and molecular clones of endogenous MLV and associated flanking cellular sequences. Finally, isolation of cellular transforming genes from MNU vs spontaneous lymphomas will be carried out by transfection studies using either molecular clones of MLV related sequences or lymphoma DNA and sib selection procedures.

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National Cancer Institute (NCI)
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Chemical Pathology Study Section (CPA)
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University of Texas MD Anderson Cancer Center
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