Friend spleen focus-forming virus (SFFV) causes a rapid, multi-stage erythroleukemia in mice due to expression of its unique envelope glycoprotein. It provides an important model for understanding the molecular changes that result in the hyperplastic, blast crisis and metastatic phases of leukemia and for testing therapeutic strategies to block each stage. Our studies have shown that the erythropoietin (Epo)-independent erythroid hyperplasia that occurs in the first stage of SFFV-induced disease is due to interaction of the viral envelope protein with a novel tyrosine kinase, sf-Stk, causing constitutive activation of signal transduction pathways for erythroid cell proliferation and differentiation. Our recent studies suggest that the erythroid specificity of SFFV-induced disease is due to the lack of expression in other cell types of sf-Stk. By co-expressing the SFFV envelope protein with sf-Stk, we have been able to transform rodent fibroblasts in vitro and cause non-erythroid malignancies in mice. Further studies using fibroblasts transformed by co-expressing the SFFV envelope protein and sf-Stk demonstrate that the interaction of the viral protein with the kinase can activate Epo signal transduction pathways associated with proliferation but not differentiation, suggesting that the Epo receptor may be required for activation of differentiation signals, such as the STAT transcription factors, by the SFFV envelope protein. The second stage of SFFV-induced erythroleukemia is characterized by the outgrowth of a rare, truly malignant erythroid cell in which SFFV has activated the myeloid transcription factor PU.1 and blocked differentiation. Our recent studies indicate that the SFFV-transformed cells are specifically blocked in their ability to phosphorylate STAT1, a transcription factor important for erythroid cell differentiation, due to high expression of the hematopoietic phosphatase SHP-1.When the transformed cells are induced to differentiate with chemicals, PU.1 and SHP-1 levels go down and STAT1 phosphorylation is restored. We recently demonstrated that SFFV-transformed erythroid cells can also undergo further molecular changes which allow them to metastasize to the bone marrow. Due to their failure to differentiate, they proliferate to such to such high levels in the bones of the skull and vertebrae that they break through into the meninges of the brain and spinal cord, causing meningeal leukemia, a frequent complication of human leukemia. Studies are in progress to determine the molecular changes responsible. Neurodegenerative disease caused by PVC-211 murine leukemia virus(MuLV), a variant of a leukemia-inducing retrovirus, provides an important model for understanding how retroviruses can undergo genetic changes that alter their interaction with cells in the host to cause novel biological effects. Our studies demonstrated that the envelope protein of PVC-211 MuLV has undergone subtle changes in its receptor binding domain that allow the virus to enter the central nervous system by efficiently infecting brain capillary endothelial cells (BCEC). We further showed that virus-infected BCEC express high levels of inducible nitric oxide synthase and the chemokine LIX and show evidence of nitric oxide production. Our recent studies suggest that damage to neurons in virus-infected animals could be the result of chronic brain hypoxia, and using NMR spectroscopy we can detect elevated levels of metabolites associated with hypoxia in the brains of PVC-211 MuLV-infected rats. Our recent data suggests that erythropoietin may be highly effective in blocking neurodegeneration induced by PVC-211 MuLV.
