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.
