The application's broad, long-term objectives are to elucidate the molecular and biochemical events involved in the pathogenesis of human hematolymphoid malignancies.
Specific aims are to isolate and define the genetic elements that are structurally altered as part of the neoplastic process and begin to study the protein products of these newly described oncogenes. These studies should provide novel DNA and antibody reagents useful for the diagnosis, subcategorization and detection of certain human malignancies and should help further our understanding of the complex subcellular pathways involved in the control of cellular proliferation and differentiation. Proposed studies will focus in part on the bcl-2 proto-oncogene, which lies at the site of t(14;18) translocations in non-Hodgkin's lymphomas. Extensive DNA cloning and sequencing studies will be carried out to further characterize genomic DNA surrounding the bcl-2 gene, various t(14;18) breakpoints, their cluster regions and potential sequence polymorphisms or somatic mutations associated with the bcl-2 gene in lymphoma patients. Antibodies will be used to carry out further biochemical and topological characterization of the Bcl-2 protein. Studies will focus on purification of the protein with a particular interest in defining potential interactions with other cellular proteins. Long-range goals are to carry out structure-function studies to correlate significant biochemical properties or associations of the protein with respective in vitro transforming activity or tumorigenesis in mice. Anti-Bcl-2 antibodies and the polymerase chain reaction will be used to screen clinical specimens to test for their potential utility in the staging and prognosis of non-Hodgkin's lymphoma patients. Recently established bcl-2 transgenic mouse strains will be further characterized for bcl-2 expression and their potential for serving as an animal model of bcl-2 induced tumorigenesis. Additional studies will focus on the characterization of translocations and candidate proto-oncogenes isolated from T-cell malignancies. Ongoing studies of the lyl-1 gene isolated from a t(7;19) breakpoint will focus on a complete structural characterization of the gene and its protein product. Antibodies will be raised against the Lyl-protein and used to carry out a preliminary biochemical characterization and subcellular localization. A second closely linked chromosome 19p13 transcriptional unit will be isolated and characterized to determine its potential role in 19p13 translocations. Pulsed-field gel analysis will be used to look for other 19p13 breakpoints, which will then be cloned and characterized. Molecular studies to characterize additional chromosomal translocations in T-cell ALL involving chromosome regions 15q22 and 11p13 will continue.
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