Monoclonal gammopathy of undetermined significance (MGUS) is a benign condition and its frequency increases dramatically with age: 1% of adults over 25, 2% of those over 50, and 20% of those over 90. It is reported to progress to multiple myeloma (MM) at a rate of 1% per year. Recently we have shown that multiple myeloma is characterized by frequent (70%) chromosome translocations involving the immunoglobulin (Ig) genes and identified four recurrent loci that are commonly involved: 11q13, 6p21, 4p16, and 16q23. The translocations result in the juxtaposition of powerful Ig enhancers adjacent to oncogenes at these loci (cyclin D1, cyclin D3, FGFR3+MMSET, and c-maf, respectively), causing their ectopic and deregulated expression in plasma cells. Using interphase FISH, IgH translocations are detected with a similar frequency in the pre-malignant MGUS. When present, they are present in every clonal cell, indicating that the translocation event precedes the clonal expansion. We hypothesize that the ectopic expression of oncogenes, as a result of IgH translocation, is the first step in the development of these clonal plasma cell expansions. We propose to study MGUS that occurs spontaneously in aging mice, develop a murine model for the generation of antigen-specific MGUS, and study the B cell clones that produce them. Such a model will allow us to isolate the cells responsible for the MGUS and study alterations in their phenotype or genotype. We will determine if these expansions share similar ectopic gene expression, evidence of numerical chromosomal abnormalities, or immunoglobulin gene translocation. We will determine the role of ongoing antigen exposure in maintaining the clone's large size. Finally, we propose to create transgenic mice in which the expression of the relevant oncogenes is controlled by Ig regulatory elements, mimicking the effect of the Ig translocation. These studies will allow us to define the role of these genetic abnormalities in the development of plasma cell neoplasms. They also provide a framework to identify and study the contribution of additional events involved in the initiation and progression of MGUS and MM.
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