Retrovirus Models of Cancer

整体项目总结 此竞争性续期申请(P01CA100730)寻求资金，以继续我们高度集成的 逆转录病毒模型阐明淋巴细胞转化的细胞机制及其相关 淋巴增生性疾病。人类逆转录病毒、人T细胞白血病病毒感染CD4+T细胞的实验研究 1型(HTLV-1)，诱导它们永生化，并使这些细胞积累基因突变 到恶性肿瘤，成人T细胞白血病(ATL)。HTLV-1模型研究的优势 白血病的发生是病毒感染所带来的T细胞永生化的快速诱导。这款车 白血病的发生可以仔细检查感染病毒的生物变化和反应模式 癌前细胞在控制并可能促进的细胞和病毒因素的影响下 进展为癌症。在上一个资助期，我们在以下方面取得了重大进展： 1)逆转录病毒辅助蛋白如何促进细胞永生；2)逆转录病毒如何引起广泛的细胞 改变感染细胞发展为转移性癌症的位置；3)以及ATL细胞如何参与 副肿瘤性疾病综合征，可作为抗癌治疗的靶点。在下一个资助期， 该项目的总体主题是继续我们对HTLV-1白血病模型的研究，重点是 发现关键的病毒、细胞和微环境因素如何协同作用促进T细胞癌。我们 现在认识到三个相互关联的研究领域，这三个领域是我们对霍乱发病机制理解的主要差距 HTLV-1相关T细胞白血病的发生：1)HTLV-1多功能hbz基因的作用机制 2)HTLV-1 CTCF-BS(11锌指CCCTC因子结合位点)对T细胞的影响 永生化，hbz表达，潜伏期的建立和对向ATL过渡的贡献；以及3) 影响HTLV-1感染T细胞存活和扩增的微环境因素及其意义 向ATL进军。

OVERALL PROJECT SUMMARY This competitive renewal application (P01CA100730) seeks funds to continue our highly integrated studies of retrovirus models to elucidate cellular mechanisms of lymphocyte transformation and associated lymphoproliferative disease. Infection of CD4+ T-cells with the human retrovirus, human T-cell leukemia virus type 1 (HTLV-1), induces their immortalization and enables those cells to accumulate genetic mutations leading to the malignant cancer, adult T-cell leukemia (ATL). The advantage of the HTLV-1 model to study leukemogenesis is the rapid induction of T-cell immortalization brought about by the viral infection. This model of leukemogenesis allows careful examination of the biologic changes and response patterns of virus infected preneoplastic cells while under the influence of cellular and viral factors that control and perhaps promote progression to cancer. In the previous funding period, we made substantial advances in our understanding of: 1) how retrovirus accessory proteins contribute to cell immortalization; 2) how retroviruses cause broad cellular changes that position infected cells to progress to a metastatic cancer; 3) and how ATL cells contribute to paraneoplastic disease syndromes, and can be targeted for anticancer therapy. In the next funding period, the overall theme of the Program Project is to continue our studies with HTLV-1 leukemia model with a focus on discovering how key viral, cellular and microenvironmental factors work in concert to promote T-cell cancer. We now recognize three interrelated areas of study that are major gaps in our understanding of the pathogenesis of HTLV-1-associated T-cell leukemogenesis: 1) Mechanism of action of HTLV-1 multifunctional hbz mRNA and HBZ protein; 2) The effect of HTLV-1 CTCF-BS (11-zinc finger CCCTC factor-binding site) on T-cell immortalization, hbz expression, establishment of latency and contribution to the transition to ATL, and; 3) Microenvironmental factors that contribute to the survival and expansion of HTLV-1-infected T-cells and their progression to ATL.