The plasma cell proliferative disorders are malignancies of B cells that all manifest as monoclonal plasma cells in the bone marrow. We believe that the clinical manifestations of multiple myeloma (MM) differ from those in monoclonal gammopathy of undetermined significance (MGUS) because of molecular and biological changes that occur in the clonal plasma cells during the progression from MGUS to MM. Since all MM cases likely originate as MGUS, understanding these biological differences could provide treatment strategies to prevent the transformation to overt MM. A key finding of our previous work has been the molecular identification of clonally related B cells in the blood of both MGUS and MM patients. The capacity of these clonally-related B cells to differentiate into mature plasma cells is currently unknown as is the significance of this population with respect to malignant transformation and disease relapse in MM following current treatment strategies. Our preliminary studies indicate that notable differences that exist between these two diseases are that plasma cells from MM patients exhibit higher growth and lower apoptotic rates than MGUS plasma cells and the marrow in MM has a higher microvessel density (angiogenesis). These differences may result from acquired overexpression of heparan sulfate proteoglycans (HSPG), such as syndecan- l, that bind fibroblast growth factors (FGFs). The mechanism(s) underlying these disease-relevant differences is currently unknown as is whether these trends are also shared by the clonally-related B cells present in both diseases. The goals of this project are to identify and characterize clonally-related B cells, determine their capacity to be differentiated to mature plasma cells, and to analyze plasma cell HSPG, FGF, and FGF receptor (FGFR) expression and learn the role of the HSPG-FGF-FGFR signaling complex in modulating myeloma cell growth and apoptosis. This work is organized into three specific aims: (l) to identify clonal cells other than plasma cells in the blood and marrow of patients with MGUS or MM and characterize their immunological, molecular, and cytogenetic features; (2) to determine the differentiation potential of clonally related B cells from the blood of patients using a well-characterized in vitro activation system; and (3) to investigate the differences in expression of FGFs and FGFRs in monoclonal plasma cells from myeloma cell lines and patients with MGUS or MM and to measure the effects of FGFs on myeloma cell proliferation and apoptosis. The results of these studies are certain to provide new insight into the key biological differences between MGUS and myeloma plasma cells as well as to guide the development of new treatment approaches that target all malignant cells.
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