Our objectives are to understand the mechanisms that can regulate the growth and differentiation of multipotential hematopoietic stem cells and how viral oncoproteins subvert these mechanisms to cause leukemia. Our studies will provide important information to unravel the mechanisms of the leukemic transformation of these cells, and will also provide the basis for the utilization of this cell type for gene therapy strategies. Terminal differentiation requires the integration of signals from cell surface receptors and nuclear signaling molecules. Similarly, leukemic transformation requires mutations in several genes for the development of a fully malignant phenotype. Thus, to understand these processes the interactions between signaling molecules have to be studied. The model system under analysis studies multipotential stem cells that have the capability to differentiate into cells of the myeloid and erythroid lineages. These cells can be induced to grow by signals from both the nuclear oncogene v-Ski and the endogenous c-kit tyrosine kinase receptor. Furthermore, interaction of signals provided by v-Ski and the oncogenic tyrosine kinase v-Sea cause stem cell leukemia. Thus, this system allows an analysis of the interaction between nuclear signals and signals from tyrosine kinases in both differentiation and leukemogenesis.
Our specific aims are: 1. To determine the mechanism of action of the v-Ski gene in inducing the growth of the multipotential cells. a) We will identify the protein(s) that v-Ski can interact with and characterize the complex; b) we will determine the role of v-Ski in the self-renewal, commitment and differentiation of the multipotential progenitor cells. 2. To determine which signal transduction pathways activated by the growth factor tyrosine kinases are important for the growth and differentiation of the multipotential cells. a) We will identify the pathways that are activated; b) using a combination of dominant negative mutants of various components of signaling cascades, together with mutations within the v-Sea kinase, we will address the role of these pathways in growth, commitment and transformation.
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