BIOLOGY OF PLASMA CELL TUMOR DEVELOPMENT

人类浆细胞肿瘤最常见的形式是多发性骨髓瘤，这是一种无法治愈的癌症。包括油和含有逆转录病毒的癌基因在内的各种因素也可以在小鼠身上诱导出类似的肿瘤。我们之前已经在这两个物种中展示了与这种疾病相关的一些共同特征。这些包括：1)T细胞在疾病进展中的作用；2)大多数肿瘤的发生绝对需要白介素6(IL-6)；3)肿瘤细胞的骨髓归巢伴随着相关的骨破坏。因此，小鼠系统似乎是一个有用的模型，既可以评估与这种形式的肿瘤相关的生化损伤，也可以开发新的治疗方法。我们最近证实了胰岛素样生长因子受体I(IGF-IR)信号通路在浆细胞肿瘤中的作用。研究发现，在油和逆转录病毒(RAF/myc)诱导的小鼠肿瘤中，IGF-IR表达上调，导致下游信号通路的结构性激活，涉及胰岛素反应底物2和磷脂酰肌醇3激酶。这一途径在第二种逆转录病毒(ABL/myc)诱导的肿瘤中也被结构性激活，因此在迄今检查的所有浆细胞肿瘤中都被解除调控。相反，在一系列B细胞肿瘤中没有观察到放松调控，因此是浆细胞疾病特有的。无论是在体外还是在体内，成分激活途径的生物学相关性都已被证明。最近对一系列骨髓瘤的研究表明，IGF-IR信号通路在人类形式的骨髓瘤中也可能是重要的。八个人类细胞系中有六个有证据表明IGF-I促进了细胞的增殖。当动物在肿瘤发展期间接受人IGF-I时，OPM-2株在SCID小鼠中生长更快的能力证明了IGF-I在体内的作用。这些结果表明，IGF-I信号通路可能在人类骨髓瘤中发挥重要作用，目前的研究旨在阐明这一通路的下游信号元件。参与浆细胞肿瘤发展的第二个主要途径涉及通过IL-6受体的信号传导。IL-6在小鼠浆细胞肿瘤的发生发展中是绝对必需的，在人类中的一些研究也同样表明在骨髓瘤的进展中起着重要作用。对IL-6途径的研究表明，紧邻受体下游的Janus kinase1(JAK1)在随后的信号事件中起着关键作用。JAK1也被认为是该家族中IL-4信号转导的关键成员。我们最近发现，浆细胞肿瘤缺乏JAK1信号的有效途径是通过IL-6和IL-4受体。此外，在存在JAK1的品系中，蛋白的磷酸化(激活)不会对IL-6或IL-4做出反应。同样，还没有发现Janus激酶家族的其他已知成员被这些细胞因子激活。这些结果表明，B系细胞中的IL-6和IL-4信号通过先前未知的中间信号分子进行。目前正在进行确定这些靶点的研究。该项目的前身是Z01 BC 05553-28 LG-细胞因子、基因治疗、癌基因、浆细胞肿瘤、信号转导、

Plasma cell tumors in humans most commonly occur as multiple myeloma, an incurable form of cancer. Similar tumors can also be induced in mice by a variety of agents including oils and oncogene containing retroviruses. We have previously demonstrated a number of common features associated with this disease in the two species. These include: 1) a role for T cells in disease progression; 2) an absolute requirement for Interleukin-6 (IL-6) for development of most tumors; 3) bone marrow homing of tumor cells with associated bone destruction. Thus, the murine system appears to be a useful model for both assessing biochemical lesions associated with this form of neoplasia as well as developing new therapeutic approaches. We have recently demonstrated a role for the Insulin-like growth factor receptor I (IGF-IR) signaling pathway in plasma cell neoplasia. IGF-IR was found to be upregulated in both oil and retroviral (raf/myc) induced murine tumors leading to constitutive activation of a downstream signaling cascade involving Insulin response substrate 2 and phosphatidylinositol 3 kinase. This pathway was also constitutively activated in tumors induced by a second retrovirus (abl/myc) and thus deregulated in all plasma cell tumors examined to date. In contrast, deregulation was not observed in a series of B cell tumors and is thus specific to plasma cell disease. The biological relevance of the constitutively activated pathway has been demonstrated both in vitro and in vivo. Recent studies with a series of myeloma lines suggest that the IGF-IR signaling pathway may also be important in the human form of this disease. Six of eight human lines evidence enhanced proliferation in response to IGF-I. An in vivo role for IGF-I was demonstrated by the ability of the OPM-2 line to grow more rapidly in SCID mice when animals received human IGF-I during the period of tumor development. These results indicate that the IGF-I signaling pathway may play an important role in human myeloma, in general, and current studies are aimed at elucidating the downstream signaling elements in this pathway.A second major pathway involved in plasma cell tumor development involves signaling through the IL-6 receptor. IL-6 is absolutely required for development of murine plasma cell tumors and a number of studies in humans similarly suggest an important role in myeloma progression. Studies of the IL-6 pathway have indicated that, immediately downstream of the receptor, Janus kinase 1 (Jak1) plays a critical role in subsequent signaling events. Jak 1 has also been identified as the critical member of this family in IL-4 signaling. We have recently determined that plasma cell tumors lacking Jak1 signal efficiently through both the IL-6 and IL-4 receptors. Furthermore, in lines in which Jak1 is present, phosphorylation (activation) of the protein does not occur in response to either IL-6 or IL-4. Similarly, no other known members of the Janus kinase family have been found to be activated by these cytokines. These results indicate that IL-6 and IL-4 signaling in B lineage cells proceeds through previously unidentified intermediary signaling molecules. Current studies are underway to identify these targets.This project was formerly Z01 BC 05553-28 LG - Cytokines, gene therapy, Oncogenes, Plasma cell tumors, Signal Transduction,