The long-term goal of this research is to provide new insights into the biology and pathogenesis of human multiple myeloma (MM), with the ultimate goal of improving the diagnosis and treatment of this fatal disease. The hypothesis to be tested is that protooncogenes, perhaps novel to multiple myeloma and heretofore unidentified, are involved in the pathogenesis of this disease. Studies of protooncogene translocation and/or activation in human multiple myeloma have been limited, due in part to the difficulty of obtaining adequate marrow plasma cell samples from myeloma patients, difficulties in karyotypic analysis, and the limited number of human myeloma cell lines. This research will focus on immunoglobulin gene loci from myelomas of aberrant immunophenotype, as these loci may be rendered non-functional by the insertion of foreign gene sequences. A tumor producing only a light chain paraprotein, for example, may have non- functional heavy gene rearrangement as a result of protooncogene insertion at the heavy chain locus on chromosome 14, a genetic event well described in other human B-cell neoplasms. One lambda light chain myeloma (EBX) studied in detail has such an aberrant heavy chain rearrangement, with an as yet unidentified sequence inserted into the immunoglobulin u switch locus.
The specific aims of this research are to complete the cloning and characterization of the EBX heavy chain insertion, to develop restriction maps of other aberrant MM immunoglobulin genes, and to clone and characterize by hybridization and DNA sequencing analysis certain flanking sequences from these aberrant genes. Finally, the protooncogene or novel sequences identified will be used as probes of genes rearrangement and mRNA expression in a broad range of myeloma tumor cells, other gammopathies, and B- cell neoplasms by Southern and Northern blot analysis. Successful completion of these studies will provide new insights into the mechanisms of non-functional immunoglobulin gene rearrangement in aberrant phenotypes of human multiple myeloma, and may reveal the translocation or activation of genes pathogenetically related to the malignant transformation or progression of this disease.
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