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

遗传改变和多发性骨髓瘤——对细胞生长的影响

• 批准号: 6563837
• 负责人: BRIAN G VAN NESS
• 金额: $ 22.84万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-06 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563837
• 关键词: apoptosis; cell growth regulation; cell proliferation; clinical research; cysteine endopeptidases; cytogenetics; gammopathy; gene expression; human subject; interleukin 1; interleukin 6; mixed tissue /cell culture; molecular oncology; multiple myeloma; neoplastic cell; neoplastic process; oncogenes; p53 gene /protein; tumor suppressor genes

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.

尽管多发性骨髓瘤（MM）是由浆细胞克隆扩增引起的，但患者之间的遗传异常存在显着的异质性。促进疾病进展和治疗反应的信号不仅影响增殖潜力，还影响细胞凋亡的诱导。本研究的目的是确定遗传异质性如何影响 MM 细胞的生长、死亡和对治疗药物的反应。在第一个具体目标中，我们将使用骨髓瘤细胞系来检查 IL-6 以及 ras、p53、Rb 和 PTP1C (SHP-1) 基因改变对细胞增殖、凋亡信号传导和治疗反应的影响。我们将通过确定如何调节 bcl-2、bcl-xL、bad 和 bax 的表达来增强或保护细胞免于凋亡，以及对 caspase l (ICE) 和 caspase 3 的影响，确定基因改变如何影响骨髓瘤细胞凋亡。我们将确定治疗剂（类固醇、细胞因子、DNA 烷基化、抗有丝分裂）在不同类型的骨髓瘤细胞中如何介导细胞凋亡。 基因改变。我们相信疾病进展或反应的异质性受到患者特异性基质相互作用的影响。因此，我们将在体外确定转基因骨髓瘤细胞对基质共培养物中治疗剂的敏感性。我们体外研究的延伸将是关联增殖和细胞凋亡对非活动性和活动性疾病进展的影响。在具体目标 2 中，我们将开发一种新型浆细胞生长指数，该指数源自标记指数和凋亡分数的测量。