MOLECULAR BASIS FOR ERYTHROLEUKEMIAS INDUCED BY MURINE RETROVIRUSES

小鼠模型系统被用来阐明该疾病的分子基础 非癌基因逆转录病毒引起的红白血病。研究 脾病灶形成病毒(SFFV)之友株的研究 扩展了之前的研究，表明唯一的信封 病毒糖蛋白通过以下途径改变红系细胞的生长 使细胞不依赖红系激素促红细胞生成素 (EPO)。为了了解SFFV包络的机制 蛋白质导致EPO独立性，进行了更好的研究 了解促红细胞生成素信号转导途径并确定它是如何 被SFFV改变。因为细胞因子受体的几个成员 超家族，EPO受体是其中的一员，已经被证明是 通过最近描述的Jak-Stat通路的信号，研究 启动以确定该途径是否被EPO和SFFV激活。 研究表明，DNA结合蛋白与国家的两个成员有关 潜伏转录因子家族，STAT1和STAT3，是瞬时的 促红细胞生成素对酪氨酸磷酸化的反应 同样的蛋白质在感染的红系细胞中被结构性激活 使用SFFV。Stat蛋白的结构性激活也是 使用感染了SFFV的小鼠的脾细胞演示并发生了 同时使用了导致红细胞增多症和贫血的病毒株。 SFFV对携带FV-2病毒的小鼠不能诱发红白血病 抗性基因似乎不是由于 易感和抗性小鼠在Jak-Stat途径诱导中的作用 促红细胞生成素。这些研究首次证明促红细胞生成素诱导 红系细胞中Stat蛋白的激活及其构成 Stat蛋白的激活可能导致白血病。研究正在进行中 促红细胞生成素活化的Stat蛋白的进一步研究进展 SFFV，可能代表独特的红系特异性DNA结合 蛋白质，并鉴定由这些蛋白激活的红系细胞中的基因 转录因子。此外，正在进行研究，以 确定SFFV包膜表达的机制 红系细胞中的糖蛋白导致结构性激活 Jak-Stat途径，并确定病毒蛋白是否也可以 激活其他可能被EPO激活的信号转导通路。

Mouse model systems are used to elucidate the molecular basis for the erythroleukemias induced by non-oncogene-containing retroviruses. Studies on the Friend strain of the spleen focus-forming virus (SFFV) have extended previous studies which showed that the unique envelope glycoprotein of the virus alters the growth of erythroid cells by rendering the cells independent of the erythroid hormone, erythropoietin (Epo). In order to understand the mechanism by which the SFFV envelope protein causes Epo independence, studies were carried out to better understand the Epo signal transduction pathway and to determine how it is altered by SFFV. Since several members of the cytokine receptor superfamily, of which the Epo receptor is a member, have been shown to signal through the recently described Jak-Stat pathway, studies were initiated to determine if this pathway was activated by Epo and SFFV. It was shown that DNA-binding proteins related to two members of the Stat family of latent transcription factors, Stat1 and Stat3, are transiently activated by tyrosine phosphorylation in response to Epo and that the same proteins are constitutively activated in erythroid cells infected with SFFV. Constitutive activation of Stat proteins was also demonstrated using spleen cells from SFFV-infected mice and occurred using both the polycythemia- and anemia-inducing strains of the virus. Failure of SFFV to induce erythroleukemia in mice carrying the Fv-2 resistance gene does not appear to be due to differences between susceptible and resistant mice in induction of the Jak-Stat pathway by Epo. These studies are the first to demonstrate that Epo induces activation of Stat proteins in erythroid cells and that constitutive activation of Stat proteins may result in leukemia. Studies are in progress to further characterize the Stat proteins activated by Epo and SFFV, which may represent unique, erythroid-specific DNA-binding proteins, and to identify the genes in erythroid cells activated by these transcription factors. In addition, studies are being carried out to determine the mechanism by which expression of the SFFV envelope glycoprotein in erythroid cells leads to constitutive activation of the Jak-Stat pathway, and to determine whether the viral protein can also activate other signal transduction pathways that may be activated by Epo.