Our studies of oncogenesis in MoMuLV induced rat thymic lymphomas have detected four putative oncogenes (Mlvi-1, Mlvi-3 and Mlvi-4) which appear to be involved in this process. Furthermore, in recent studies aiming at the dissection of the genetic events that occur in the early (tumor induction) and late (tumor progression) stages of oncogenesis we have shown that: a) the spleens of preleukemic animals contain populations of cells that are clonal with regard to provirus insertion, and b) tumor progression is associated with provirus reintegration in tumor cell DNA. The objectives of this work are: a) to determine the role of loci targeted by provirus integration during oncogenesis, b) to determine the mechanism and the significance of provirus reintegration during tumor progression and c) to exploit provirus integration as a marker to determine the nature and fate of preleukemic cells and the mechanism of segregation of leukemic cells in a single tumor bearing animal. The study of the molecular events involved in the induction and progression of rat thymic lymphomas may provide information directly applicable to the understanding of the biology of human lymphoid neoplasms. The work proposed here aims at: I. The characterization of the Moloney leukemia virus integration (MLvi) loci in the rat and II. The analysis of the role of provirus integration in tumor induction and progression. To achieve these goals we will utilize the following methodology: Southern and Northern blotting, pulse field gradient gel electrophoresis, cloning of genomic DNA and cDNA, DNA sequence analyses, immune precipitation and Western blotting, S1 and primer extension mapping of mRNA transcripts, raising of antibodies, transfection, electroporation, transplantation of preleukemic and leukemic cells into recipient animals, and culture of normal and tumor cells.
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