THE C-KIT PROTOONCOGENE IN NORMAL AND MALIGNANT HUMAN HEMATOPOIESIS

The c-kit proto-oncogene encodes a tyrosine kinase receptor (KIT) which is expressed on many types of human cells, including approximately 4% of bone marrow mononuclear cells. Numerous studies attest to the importance of the c-kit receptor and its ligand, known variously as stem cell factor (SCF), mast cell growth factor (MGF), Steel factor (SF), or kit ligand (KL) (the nomenclature we prefer), in the development of human hematopoietic cells. KL, which is produced in membrane-bound and soluble forms by bone marrow stromal cells, acts on pre-colony forming units (pre-CFU) and CFU cells. In synergistic combination with other cytokines, KL enhances the growth of myeloid progenitor cells. However, using an antisense oligodeoxynucleotide strategy to disrupt c-kit function, we have demonstrated that the KL-KIT complex is of greatest importance for generation and/or proliferation of normal human erythropoietic progenitor cells. In malignant hematopoietic cells, the complex also appears to be important for growth of granulocyte/macrophage (GM) CFU as well.