MOUSE MODELS TO STUDY THE ROLE OF TRAF1 AND TRAF2 IN THE ETIOLOGY OF LEUKEMIA

描述（由申请人提供）：TRAFs是TNF受体（TNFR）家族信号转导的出现点。它们整合来自TNFR家族许多成员的信号，调节NF"B和c-jun，基因表达的重编程和细胞死亡的控制。这些途径的放松是导致一些自身免疫性和炎症性疾病的原因。越来越多的证据表明，TRAF2可能在控制B细胞稳态中起作用。缺乏TRAF2的B细胞在转基因小鼠中具有生存优势和积累。此外，我们最近描述了在B淋巴细胞中过表达Bcl-2和缺乏n端环和锌指结构域的TRAF2突变体（TRAF2DN）的转基因小鼠，它模仿TRAF1，发展为小B细胞淋巴瘤和白血病，具有与人类慢性淋巴细胞白血病（CLL）非常相似的特征。这些结果提供了第一个直接证据，证明trf信号通路的解除可能与肿瘤发生有关。TRAF1可能调节traf2介导的活动和亚细胞定位。有趣的是，我们和其他人已经表明，TRAF1在一些人类造血恶性肿瘤中高度过表达，如非霍奇金淋巴瘤（NHL），特别是慢性淋巴细胞白血病（CLL）。然而，目前尚不清楚TRAF1上调是否在疾病的发生和/或进展中起作用。我们推测TRAF1过表达直接参与B细胞恶性肿瘤的发展或维持。我们打算在B细胞中产生特异性表达TRAF1的转基因小鼠。这些小鼠将有助于回答TRAF1是否使B细胞对恶性肿瘤敏感的问题。此外，我们将阐明TRAF1是否与Bcl-2协同发展CLL。此外，我们将进一步表征由TRAF2DN/Bcl-2小鼠发展的cll样白血病，使用其他技术中的cDNA阵列来确定该肿瘤细胞中的特定表达模式。我们的目标是验证这些小鼠作为化疗药物测试的临床前模型。因此，本提案的目的是：1。在B淋巴细胞中表达TRAF1的转基因小鼠的产生。2. 目的：探讨TRAF1在B细胞恶性易感性中的作用。B细胞中TRAF2DN和Bcl-2过表达引起的cll样淋巴细胞增生性疾病的特征

DESCRIPTION (provided by applicant): TRAFs are the point of emergence of TNF Receptor (TNFR)-family signal transduction. They integrate the signaling from many members of the TNFR family and regulate NF"B and c-jun, the reprogramming of gene expression, and the control of cell death. Deregulation of these pathways is causative of several autoimmune and inflammatory diseases. There is growing evidence indicating that TRAF2 might have a role in controlling B cell homeostasis. B cells lacking of TRAF2 have survival advantages and accumulate in transgenic mice. Furthermore, we have recently described that transgenic mice over-expressing in B lymphocytes both Bcl-2 and a TRAF2 mutant lacking the N-terminal RING and zinc finger domains (TRAF2DN), which mimics TRAF1, develop small B cell lymphoma and leukemia that have remarkably similar characteristics to human chronic lymphocytic leukemia (CLL). These results have provided the fist direct evidence that deregulation of TRAF signal pathways might be implicated in tumorigenesis. TRAF1 might regulate TRAF2-mediated activities and subcellular localization. Interestingly, we and others have shown that TRAF1 is highly over-expressed in some human hematopoietic malignancies, such as non-Hodgkin lymphomas (NHL) and particularly in chronic lymphocytic leukemias (CLL). However it is not clear whether or not TRAF1 upregulation has a role in the development and/or progression of the disease. We speculate that TRAF1 overexpression is directly involved in the development or maintenance of B cell malignancies. We propose to generate transgenic mice specifically expressing TRAF1 in B cells. These mice will help to answer the question on whether TRAF1 sensitizes B cells to malignancy. Also, we will elucidate whether TRAF1 cooperate with Bcl-2 in developing CLL. Furthermore we will further our characterization of the CLL-like leukemia developed by the TRAF2DN/Bcl-2 mice, using among other techniques cDNA arrays to determine the specific patterns of expression in this tumor cells. Our goal is to validate these mice as a preclinical model for chemotherapeutical drug testing. Therefore, the Aims of this proposal are: 1. Generation of transgenic mice expressing TRAF1 in B lymphocytes. 2. To assess the role of TRAF1 in predisposing B cells to malignancy and 3. Characterization of the CLL-like lymphoproliferative disorder caused by overexpression of TRAF2DN and Bcl-2 in B cells.