Hematopoiesis is the process by which hematopoietic precursor cells undergo self-renewal and differentiation into the various mature blood cell lineages. Growth factor-receptor interactions play a significant role in the regulation of normal hematopoiesis, affecting both proliferation and differentiation of various hematopoietic lineages. Alterations of these receptors plays an important role in myelodysplasia and leukemogenesis. The kit proto-oncogene encodes for a tyrosine-kinase transmembrane receptor that is expressed on very early hematopoietic precursor cells, and is involved in stem cell migration and differentiation. The growth factor ligand for the kit receptor, known as stem cell factor, has been recently purified. The purpose of our study is to investigate the role of growth factor-receptor interactions on the regulations of hematopoiesis. We will investigate the role of the kit receptor in hematopoiesis by studying its expression and tyrosine kinase activity in both cultured cell lines and in hematopoietic cells isolated from bone marrow samples from human subjects. Expression of the kit receptor will be easily monitored using a monoclonal antibody which we have developed. The effects of various cytokines, including stem cell factor, on cells that express the kit receptor will be studied. Finally we will look for abnormal kit expression and/or function in patients with hematological disorders including leukemias, myelodysplastic disorders, and congenital anemias. Those patients whose cells show abnormal kit expression or function will be further investigated to define the defect at the molecular level. These studies should enhance our knowledge of the role of growth factor-receptor interactions in normal and abnormal states o hematopoiesis, thus leading to a better understanding of the pathophysiology of certain hematological diseases, and possibly lead to better therapies for these diseases.
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