The hematopoietic system functions throughout the life of an animal to produce the mature cells of the myeloid, erythroid and lymphoid lineages. This system is controlled by a complex network of cell surface interactions involving both cell-cell and cell-growth factor systems. Leukemia can be viewed as a breakdown in these regulatory interactions. Our objectives are to identify these important interactions which control the growth and differentiation of hematopoietic cells in order to identify mechanisms that could acute leukemia provide a unique system to investigate possible mechanisms by which this network can be perturbed. The avian retroviruses that cause erythroblastosis are a particularly attractive model system in that they provide a system where hematopoietic cells can be transformed in vitro, the oncogene products are membrane glycoproteins, and temperature sensitive mutants are available which allow the oncogene to be inactivated. Therefore it is possible to study the interaction of the viral oncogene with the cell and to identify mechanisms by which the growth of of the cells can be perturbed; in addition, following thermal inactivation of the oncogene, normal cellular regulatory molecules which are playing important roles in controlling the subsequent differentiation can be identified. In this proposal our specific aims are: 1. to characterize, the oncogene of the avian erythroblastosis virus S13 by molecularly cloning the provirus and identifying the oncogene product responsible for cell transformation; 2. to use existing temperature mutants of S13 and avian erythroblastosis virus strain ES4 to investigate the interaction of the oncogenes of these two viruses with erythroid cells; and 3. to use the temperature sensitive S13 and AEV transformed erythroblasts together with monoclonal antibodies against erythroid surface antigens to identify normal cell surface receptors that play a role in the differentiation of erythroid cells, in particular the chicken transferrin receptor.
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