MECHANISMS OF MYELOMA CELL GROWTH CONTROL

多发性骨髓瘤是一种普遍致命的疾病，其特征在于恶性浆细胞在骨髓中的积聚。骨髓瘤细胞的生长特征与正常终末期浆细胞的生长特征形成鲜明对比。正常B细胞终末分化的分子调控尚不完全清楚，然而，据信这种调控涉及转录因子的激活，所述转录因子是驱动基因表达所必需的，所述基因的产物对分化的表型是特异性的。白细胞介素6（IL-6）是驱动正常B细胞分化的外部信号的重要实例;然而，它在对细胞生长没有任何影响的情况下这样做。相比之下，IL-6在侵袭性骨髓瘤患者中作为恶性浆细胞的有效生长因子发挥作用。因此，我们假设骨髓瘤细胞对IL-6的反应性改变，即，生长而不是分化，并且作为这种IL-6响应性的结果，IL-6刺激的基因表达中存在关键变化。关于IL-6介导的JAK/STAT和Ras-MAP激酶（Ras-MAPK）通路的激活存在大量信息，然而，在IL-6介导的骨髓瘤细胞生长中，任一通路的作用尚未确定。Pi先前已经建立了一组IL-6应答的人骨髓瘤细胞系，并且在正常人B细胞和浆母细胞的研究中也具有重要的专业知识。因此，她是唯一的定位，以分析骨髓瘤细胞生长中这些良好表征的信号通路的作用。具体目标包括：（1）确定JAK/STAT活化途径在IL-6驱动的骨髓瘤细胞增殖中的重要性;（2）确定Ras/MAPK活化途径在IL-6驱动的骨髓瘤细胞增殖中的重要性;和（3）鉴定和表征IL-6信号转导通路的遗传靶点应用差异显示逆转录聚合酶链反应和cDNA阵列分析技术，

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 include: (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.