Multiple chromosomal and genetic abnormalities have been described in MGUS, SMM and MM, and are thought to beimportant for disease pathogenesis and disease progression. The two most common abnormalities are translocationsinvolving the immunoglobulin heavy chain locus (IgH) and aneuploidy. We and others have recently found that certaincytogenetic abnormalities have specific association patterns allowing for the cytogenetic subclassification of the disease.This has allowed the paradigm change that states that MM is not one disease, but rather several, that may be bestdiscerned according to the underlying cytogenetic aberrations. We question; Can we establish that IgH translocations are seminal events in the pathogenesis of some patients with MGUS andMM? Can we better describe the transcriptional upregulation consequences of the IgH translocations? Can the study of MGUS and MM cytogenetics further elucidate pathogenic pathways for the disease? Do patients that develop MGUS and MM have an underlying susceptibility to acquire IgH translocations?SPECIFIC AIM 1: We wish to validate the biologic importance of IgH translocations for the pathogenesis of PCneoplasms. To do this we propose to determine the actual proportion of PCs in MGUS that share signature IgHtranslocation using simultaneous clg-FISH and ASO mRNA FISH. We also wish to establish the persistence, andpotential expansion of PCs with IgH translocations in serial samples of MGUS/MM and subclones of the human MM celllinesSPECIFIC AIM 2: We will determine whether there are genetic subcategories of MGUS as in MM, Le. hyperdiploid andnon-hyperdiploid MGUS. To do so we proposed detailed description of the disease using interphase FISH and byperforming supervised clustering analysis of the gene expression profiles of MGUS and MM according to thecytogenetic category; primary IgH translocations, secondary IgH translocations and no IgH translocations.
SPECIFIC AIM 3 : Lastly we believe there is a possibility of inherent predisposition to IgH translocations in patients withMGUS and MM with IgH translocations. To find whether such a propensity exist we propose to use surrogate markersof DNA repair problems in patients at risk for MGUS and MM. We will then study the peripheral blood of patients withvarious PC proliferative disorders to detect and quantify 19HIbcl-2 PCR products.

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Mayo Clinic, Rochester
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