Retrovirus Models of Cancer

总体项目摘要 这一竞争性更新申请（P01 CA 100730）寻求资金，以继续我们的高度综合研究， 逆转录病毒模型，以阐明淋巴细胞转化的细胞机制和相关的 淋巴组织增生性疾病用人逆转录病毒、人T细胞白血病病毒感染CD 4 + T细胞 1型（HTLV-1），诱导其永生化，并使这些细胞积累基因突变， 成人T细胞白血病（ATL）HTLV-1模型研究的优势 白血病发生是由病毒感染引起的T细胞永生化的快速诱导。该模型 白血病发生的研究可以仔细检查病毒感染后的生物学变化和反应模式， 癌前细胞，同时在细胞和病毒因素的影响下，控制和可能促进 进展为癌症。在上一个资助期间，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化; 2）逆转录病毒如何引起广泛的细胞增殖 改变受感染细胞的位置，使其发展为转移性癌症; 3）以及ATL细胞如何有助于 副肿瘤疾病综合征，并且可以作为抗癌治疗的靶点。在下一个资助期内， 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工作，以促进T细胞癌症。我们 现在认识到三个相互关联的研究领域，这是我们理解发病机制的主要差距。 HTLV-1相关的T细胞白血病发生：1）HTLV-1多功能hbz mRNA和 HTLV-1 CTCF-BS（11-zinc finger CCCTC factor-binding site）对T细胞增殖的影响 永生化、hbz表达、潜伏期的建立和对向ATL转变的贡献，以及; 3） 有助于HTLV-1感染的T细胞的存活和扩增的微环境因素及其作用 升级到ATL。

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.