HEMATOPOIESIS DEPENDS ON GROWTH FACTOR

THE PROLIFERATION and differentiation of blood cellprogenitors and precursors are tightly regulated by ap-proximately a dozen different growth factors, which act primar-ily on hematopoietic cells.1 In addition, growth factors that stimulate a wider variety of cell types, such as insulin-like growth factor 1, are also able to stimulate the proliferation of hematopoietic progenitor cells.2 Both types of growth factors activate receptor-mediated tyrosine kinase signaling pathways. Acting as extracellular signals, hematopoietic growth factors bind to cell-surface receptors and induce a rapid increase in tyrosine phosphorylated cellular proteins. Tyrosine phosphory-lation of growth factor receptors and cytoplasmic signaling molecules then serves to amplify the intracellular signal and activate a diverse number of intracellular signaling pathways. These signaling pathways suppress apoptosis and induce the transcription of genes required for mitogenesis. Many of the same signaling molecules are also activated by growth factors that stimulate terminal differentiation, rather than proliferation, of precursor cells. The receptors for three well-established hematopoietic growth factors, macrophage colony-stimulating factor (M-CSF), stem cell factor (SCF), and the Flt-3 ligand, are transmembrane tyrosine kinases in which the cytoplasmic domain of these receptors encodes a tyrosine kinase.3-8 Ligand binding leads to receptor dimerization and immediate activation of the receptor tyrosine kinase domain. In contrast, the receptors for the majority of hematopoietic growth factors, including granulo-cyte CSF (G-CSF), GM-CSF, erythropoietin (Epo), thrombopoi