BIOLOGY OF PLASMA CELL TUMOR DEVELOPMENT

一、白介素6(IL-6)已被证明是主要的增长 小鼠浆细胞瘤和人浆细胞瘤发生发展的相关因素 骨髓瘤。IL-6基因失活的小鼠具有抵抗力 对肿瘤的诱导，如肿瘤未能发展所证明的 在用含有raf和myc癌基因的逆转录病毒治疗后。 然而，当RAF被ABL取代时，这些小鼠会发展成肿瘤， 提示IL-6非依赖性肿瘤可以由其他 癌基因组合或突变。我们之前已经证明过 细胞因子非依赖性肿瘤的发生机制是通过 IL-6信号转导通路的结构性激活。近期 研究表明，ABL直接与IL-6受体结合。 然而，受体不被ABL和即刻的 下游信号分子JAK1和JAK2也是 去磷酸化的。ABL已被发现直接与STAT3结合， IL-6中的主要信号转导和转录激活因子 途径，随后该分子的磷酸化导致 该途径的结构性转录激活。这个系统有 进一步用于评估ABL在以下方面的其他交互作用 可能是细胞过程的失调。ABL已被发现 与PI-3激酶途径中的分子相互作用的实验是 目前正在确定ABL可以通过哪些具体机制 激活这条通路。 二、人类模型的开发研究仍在继续 用小鼠浆细胞瘤评价骨髓瘤的基因治疗 疾病治疗的方法。两者之间的主要区别之一是 人骨髓瘤和小鼠浆细胞肿瘤与组织的关系 本地化。在早期疾病中，骨髓瘤主要局限于 骨髓和骨骼疾病是常见的并发症。BALB/C等离子体 在腹膜腔诱发细胞肿瘤和骨髓疾病 而骨骼受累还没有得到评估。目前的研究已经 证明了几种小鼠肿瘤会导致骨髓疾病。 对S107系的详细分析表明优先选择骨髓 一周后在骨髓中检测到肿瘤细胞的归巢 在注射后，但在其他器官中缺失。肿瘤细胞 随后传播到与终末相似的各种器官 人类疾病的阶段。与破骨细胞相关的骨破坏 当肿瘤细胞在骨髓中扩张时，可观察到肿瘤受累。一条支线 是从骨髓中分离出来的定位亲代肿瘤 没有偏好地播种所有器官，从而提供了一种模型 确定影响肿瘤细胞能力的分子事件 从骨髓传播到其他器官。上述内容 人类和小鼠浆细胞疾病的相似性表明 小鼠模型在开发治疗药物方面可能很有价值。 人类疾病的方法。

I. Interleukin-6 (IL-6) has been demonstrated to be the major growth factor involved in development of murine plasma cell tumors and human myeloma. Mice in which the IL-6 gene has been inactivated are resistant to tumor induction as evidenced by the failure of tumors to develop following treatment with retroviruses containing raf and myc oncogenes. However, these mice develop tumors when raf is replaced by abl, suggesting that IL-6 independent tumors can be generated either by other oncogene combinations or mutations. We have previously demonstrated that the mechanism by which cytokine independent tumors arise is through constitutive activation of the IL-6 signal transduction pathway. Recent studies have indicated that abl binds directly to the IL-6 receptor. However the receptor is not phosphorylated by abl and the immediate downstream signaling molecules, Jak1 and Jak2, are also unphosphorylated. Abl has been found to directly bind to STAT3, the major signal transducer and activator of transcription in the IL-6 pathway, and subsequent phosphorylation of this molecule leads to constitutive transcriptional activation of the pathway. This system has further been used to evaluate other interactions of abl with regard to possible dysregulation of cellular processes. Abl has been found to interact with molecules in the PI-3 kinase pathway and experiments are currently in progress to determine specific mechanisms by which abl may activate this pathway. II. Studies have continued on the development of a model for human myeloma using mouse plasma cell tumors to evaluate gene therapy approaches to disease treatment. One of the major differences between human myeloma and murine plasma cell tumors relates to tissue localization. In early stage disease, myeloma is largely restricted to bone marrow and bone disease is a frequent complication. BALB/c plasma cell tumors are induced in the peritoneal cavity and bone marrow disease and bone involvement have not been evaluated. Current studies have demonstrated that several murine tumors produce bone marrow disease. Detailed analysis of the S107 line demonstrates preferential bone marrow homing in that tumor cells are detected in the marrow at one week following injection, but are absent from other organs. Tumor cells subsequently disseminate to a variety of organs resembling the terminal phase of human disease. Bone destruction associated with osteoclast involvement is observed as tumor cells expand in the marrow. A sub-line has been isolated from the marrow localizing parental tumor which now seeds all organs without preference and thus provides a model to determine the molecular events effecting the ability of tumor cells to disseminate from bone marrow to other organs. The above described similarities between human and murine plasma cell disease suggest that the mouse model is likely to be valuable in developing therapeutic approaches to human disease.