PROLIFERATIVE EFFECTS OF HTLV-1

描述（由申请人提供）：HTLV-1是成人T细胞白血病淋巴瘤（ATLL）的病原体。ATLL细胞的特点是组成性NF？B活化，其他淋巴瘤、骨髓瘤和实体瘤的关键特征。Tax癌蛋白是NF？B激活。我们以前的研究表明，经典的，特别是，替代NF？B途径在赋予细胞凋亡抗性中至关重要。目前的研究将使用创新的，生理淋巴瘤模型，以确定在肿瘤发生的作用，每个NF？B途径，并确定关键NF？负责这些作用的B靶基因。目标1。哪个NF？B通路在人源化小鼠HTLV肿瘤发生中起关键作用？在这项研究中，一种新的人源化小鼠模型用于HTLV-1感染和淋巴瘤的发展。我们将使用病毒变异表达税务突变体的缺陷，在激活替代NF？B途径或两者NF？B途径，以确定其在疾病发病机制中的作用。一种新的高通量病毒整合试验用于监测这些实验过程中感染细胞的克隆性。目标2.哪个NF？Tax转基因肿瘤的维持和进展需要B靶点？在这项研究中，一个新的诱导税收转基因小鼠淋巴瘤模型是用来评估特定的NF？使用微阵列分析肿瘤进展中的B靶基因。目标3：哪个NF？B靶基因对HTLV转化至关重要？在这项研究中，NF？B1（p105）和NF？B2（p100）用于评估每个单独的通路。表达这两种shRNA之一的HTLV-1转化细胞将进行微阵列分析，以确定哪种途径负责激活特定靶基因。此外，他们的贡献选择NF？将评估抗细胞凋亡的B靶基因。预期这些生理学相关小鼠模型的信息将鉴定在ATLL或其他淋巴瘤的治疗试验中可能被抑制的关键靶基因。

DESCRIPTION (provided by applicant): HTLV-1 is the etiological agent of adult T-cell leukemia lymphoma (ATLL). ATLL cells are characterized by constitutive NF?B activation, a key feature of other lymphomas, myeloma, and solid tumors. The Tax oncoprotein is the key viral determinant for NF?B activation. Our previous studies showed that the classical and especially, the alternative NF?B pathways were critical in conferring resistance to apoptosis. The current study will use innovative, physiological lymphoma models to define the role in tumorigenesis of each NF?B pathway and identify the key NF?B target gene responsible for these effects. Aim 1. Which NF?B pathway is critical for HTLV tumorigenesis in humanized mice? In this study, a new humanized mouse model is used for HTLV-1 infection and lymphoma development. We will use viral variants expressing Tax mutants with defects in activating the alternative NF?B pathway or both NF?B pathways, in order to define their role in disease pathogenesis. A novel high-throughput viral integration assay is used to monitor clonality of infected cells over the course o these experiments. Aim 2. Which NF?B targets are required for maintenance and progression of Tax transgenic tumors? In this study, a new inducible Tax transgenic mouse model of lymphoma is utilized to assess the role of specific NF?B target genes in tumor progression using microarray analysis. Aim 3. Which NF?B target genes are critical for HTLV transformation? In this study, shRNAs to NF?B1 (p105) and NF?B2 (p100) are used to assess each individual pathway. HTLV-1 transformed cells expressing one of both of these shRNAs will be subjected to microarray analysis to determine which pathway is responsible for activation of specific target genes. Moreover, their contribution of select NF?B target genes to resistance to apoptosis will be assessed. It is expected that the information these physiologically relevant mouse models will identify key target genes that may be inhibited in therapeutic trials of ATLL or other lymphomas.