GENETIC ALTERATIONS AND MYLTIPLE MYELOMA--EFFECTS ON CELL GROWTH & APOPTOSIS

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Although multiple myeloma (MM) results from a clonal expansion of plasma cells, there is significant heterogeneity in genetic abnormalities among patients. Contributing to disease progression and response to therapy are signals that affect not only the proliferative potential but also induction of apoptosis. The goal of this study is to characterize how genetic heterogeneity affects the growth, death and response of MM cells to therapeutic agents. In the first Specific Aim we will use myeloma cell lines to examine the effects of IL-6 and genetic alterations in ras, p53, Rb, and PTP1C (SHP-l) on cell proliferation, apoptotic signaling, and therapeutic response. We will determine how genetic alterations affect apoptosis in myeloma by determining how expression of bcl-2, bcl-xL, bad and bax are regulated to enhance or protect cells from apoptosis, and the influence on caspase l (ICE) and caspase 3. We will determine how apoptosis is mediated by therapeutic agents (steroids, cytokines, DNA alkylating, anti- mitotic) in myeloma cells with different genetic alterations. We believe that heterogeneity in disease progression or response is influenced by patient specific stromal interactions. Therefore, we will determine in vitro sensitivities of genetically altered myeloma cells to therapeutic agents in stromal co-cultures. An extension of our in vitro studies will be to correlate the influence of proliferations and apoptosis on disease progression in inactive and active disease. In Specific Aim 2 we will develop a novel plasma cell growth index that will be derived from the labeling index and measures of apoptotic fraction.