RNA Tumor Virus-Hematopoietic cell Interaction

描述（由申请人提供）：Abelson小鼠白血病病毒（Ab-MLV）转化长期以来一直是了解含有v-onc基因的逆转录病毒诱导肿瘤和转化细胞动力学的有价值的模型。该病毒提供了一种简单的遗传工具，用于检测刺激生长、抑制细胞凋亡和改变分化的信号与肿瘤抑制基因信号的交互方式。B系细胞感染Ab-MLV不可避免地导致转化和肿瘤诱导。这是一个快速的过程：体外感染的细胞在病毒整合和v-Abl蛋白表达后不久就开始分裂，感染的小鼠在感染后20至30天死亡。尽管如此，转型之路并不平坦。刺激细胞生长、抑制细胞分化和凋亡的病毒信号会被细胞反应所抵消，从而促进细胞凋亡和不稳定的生长。了解病毒如何对抗细胞反应并揭示有利于恶性生长的平衡途径将对我们对恶性疾病的理解具有广泛的意义，并阐明赋予Ab-MLV和其他含有v-onc基因的逆转录病毒致癌特性的特征。在Ab-MLV系统中，p53通路在大多数转化子中失活，在某些情况下，细胞获得p53突变，在其他情况下，p53调节蛋白p19Arf下调。我们正在利用这种病毒来了解来自病毒的信号如何对抗宿主介导的抗肿瘤作用；我们将研究四个目标：1。p53如何影响Ab-MLV感染的结果？2. Ink4a/Arf基因座的产物如何影响Ab-MLV的转化？3. p53和Ink4a/Arf基因座在体内是如何影响肿瘤诱导的？4.Ab-MLV的靶细胞特异性是如何控制的？

DESCRIPTION (provided by applicant): Abelson murine leukemia virus (Ab-MLV) transformation has long been a valuable model to understand the dynamics by which retroviruses containing v-onc genes induce tumors and transform cells. The virus provides a simple genetic tool to examine the way in which signals that stimulate growth, suppress apoptosis and alter differentiation interface with signals from tumor suppressor genes. Ab-MLV infection of B lineage cells invariably leads to transformation and tumor induction. This is a rapid process: cells infected in vitro begin to divide soon after viral integration and expression of the v-Abl protein, and infected mice succumb 20 to 30 days post infection. Despite this, the road to transformation is not a smooth one. Viral signals that stimulate cell growth and suppress differentiation and apoptosis are countered by a cellular response that promotes apoptosis and erratic growth. Understanding how the virus counters the cellular response and uncovering the pathways that tip the balance in favor of malignant growth will have broad implications for our understanding of malignant disease and illuminate the features that confer oncogenic properties to Ab-MLV and other v-onc gene-containing retroviruses. In the Ab-MLV system, the p53 pathway is inactivated in most transformants, in some instances, the cells acquire p53 mutations and in others, the p53 regulatory protein, p19Arf is down modulated. We are using the virus to understand how signals from the virus counter anti-tumor effects mediated by the host; We will investigate four aims: 1. How does p53 influence the outcome of Ab-MLV infection? 2. How do the products of the Ink4a/Arf locus influence Ab-MLV transformation? 3. How do the p53 and Ink4a/Arf loci affect tumor induction in vivo? 4.: How is the target cell specificity of Ab-MLV controlled?