MOLECULAR BASIS FOR ERYTHROLEUKEMIAS INDUCED BY MURINE RETROVIRUSES

使用小鼠模型系统来阐明免疫调节的分子基础。 由不含癌基因的逆转录病毒诱导的红白血病。研究 对脾病灶形成病毒（SFFV）的Friend株有 扩展了以前的研究，这些研究表明， 病毒的糖蛋白通过以下方式改变红系细胞的生长： 使细胞不依赖于红细胞激素促红细胞生成素 （Epo）。 为了了解SFFV包膜的机制， 蛋白质导致Epo的独立性，研究进行了更好的 了解Epo信号转导通路，并确定它是如何 被SFFV改变。 由于细胞因子受体的几个成员 Epo受体是其成员之一的超家族已被证明 通过最近描述的Jak-Stat通路，研究 启动以确定该途径是否被Epo和SFFV激活。 结果表明，DNA结合蛋白与两个国家成员有关， 一个潜在的转录因子家族，Stat 1和Stat 3， 激活的酪氨酸磷酸化，并认为， 相同的蛋白质在感染的红系细胞中被组成性激活 关于SFFV Stat蛋白的组成性激活也是 使用来自SFFV感染小鼠的脾细胞证实， 同时使用红细胞增多症和贫血症诱导病毒株。 SFFV不能诱导携带Fv-2的小鼠发生红白血病 抗性基因似乎不是由于 敏感和耐药小鼠在诱导Jak-Stat途径中的作用 EPO. 这些研究首次证明了Epo诱导 红系细胞中Stat蛋白的激活和组成性 Stat蛋白的激活可导致白血病。 研究正在 进一步表征Epo激活的Stat蛋白的进展， SFFV可能代表独特的红系特异性DNA结合 蛋白质，并确定红细胞中的基因激活这些 转录因子 此外，正在进行研究， 确定表达SFFV包膜的机制 红系细胞中的糖蛋白导致红系细胞的组成性激活， Jak-Stat途径，并确定病毒蛋白是否也可以 激活其他可能被Epo激活的信号转导途径。

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.