Four tumor-related events have been identified in MoMuLV-induced rat thymic lymphomas: DNA rearrangements predominantly due to provirus DNA integration in the Mlvi-1 and Mlvi-2 provirus integration domains, DNA rearrangements in the c-myc locus, and rearrangements in the immunoglobulin heavy chain locus. The overall objective of this research is to describe the role of these rearrangements in the induction and/or progression of rat thymic lymphomas. Since preliminary evidence indicates that sequences homologous to Mlvi-2 are rearranged in human diffuse, poorly-differentiated lymphocytic lymphomas, this work may provide information directly applicable to the understanding of human neoplasia. This work aims at: (1) the characterization of the genetic structure of the Mlvi-1 and Mlvi-2 and the elucidation of the role of DNA rearrangements in the domain of these DNA regions on their transcriptional and translational activity; (2) the examination of the ability of sequences in the Mlvi-1 and Mlvi-2 integration domains to influence oncogenesis; (3) the investigation of the temporal relationship of Mlvi-1, Mlvi-2, c-myc, and immunoglobulin heavy-chain locus rearrangements during oncogenesis (if they all occur in the same population of tumor cells); and (4) the investigation of the hypothesis that provirus integration in Mlvi-1 and Mlvi-2 is due to specificity in the selection of the provirus integration cellular DNA substrate. To achieve these goals we will utilize the following methodology: Southern and Northern blotting, molecular cloning, DNA sequence analyses, R loop analysis of cellular RNA and heteroduplex analysis of cloned DNA fragments, RNA-DNA hybridization-protection experiments, transfection experiments, culture of tumor cells for the establishment of cell lines, and in situ hybridization of cloned DNA probes to metaphase chromosomes. (X)
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