Multiple myeloma is a universally fatal disease characterized by the accumulation of malignant plasma cells in the bone marrow. The growth characteristics of myeloma cells are in striking contrast with those of normal end-stage plasma cells. The molecular regulation of normal B cell terminal differentiation is incompletely understood, however, it is believed that this regulation involves the activation of transcription factors that are necessary to drive expression of genes whose products are specific to the differentiated phenotype. Interleukin 6 (IL-6) is an important example of an external signal that drives normal B cell differentiation; however, it does so in the absence of any effect on cell growth. In contrast, IL-6 functions as a potent growth factor for malignant plasma cells in patients with aggressive myeloma. We have, therefore, hypothesized that myeloma cells display an altered responsiveness to IL-6, i.e., growth rather than differentiation, and as a result of this IL-6 responsiveness, there are key changes in IL-6-stimulated gene expression. Considerable information exists regarding IL-6-mediated activation of the JAK/STAT and Ras-MAP kinase (Ras-MAPK) pathways, however, the role of either pathway has not been established in IL-6 mediated myeloma cell growth. The Pi previously has established a panel of IL-6-responsive human myeloma cell lines and also has significant expertise in the study of normal human B cells and plasmablasts. She is, therefore, uniquely positioned to analyze the role of these well-characterized signaling pathways in myeloma cell growth.
The specific aims i nclude: (l) to determine the importance of the JAK/STAT activation pathway in IL-6 driven myeloma cell proliferation; (2) to determine the importance of the Ras/MAPK activation pathway in IL-6 driven myeloma cell proliferation; and (3) to identify and characterize the genetic targets of IL-6 signal transduction pathway(s) in myeloma by utilizing differential display reverse transcription polymerase chain reaction and cDNA array analysis.
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