The overall goals of the proposal are to better understand how feline leukemia virus (FeLV) results in selective erythroid marrow failure and how normal and neoplastic stem cells interact in the evolution of virus-induced myelodysplasia or leukemia. Further studies are outlined to define the mechanisms underlying pure red cell aplasia (PRCA) in cats infected with FeLV-C/Sarma. In order to study the clonal evolution of hematologic diseases prior to clinically evident neoplasia, we have developed a unique G-6-PD heterozygous cat model. Using this model we will study the evolution of myeloproliferative diseases and leukemia in animals infected with FeLV-AB/GM-1 or FeLV-B/Gardner Arnstein. Infection of hematopoietic cells will be carried out both in vivo and in long-term marrow culture to assess the behavior of normal versus transformed and presumably neoplastic stem cells. Furthermore, we will construct a virus combining FeLV-C and the erb-B oncogene. We predict that erythroleukemia will develop in infected animals. Finally, using the G-6-PD heterozygous model, we will study issues of clonal succession and cycling in cats supported by relatively few stem cells. This model will be generated through the repeated use of myelosuppressive drugs such as dimethylmyleran or through autologous bone marrow transplantation employing low numbers of hematopoietic cells.
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