G-csf and Myeloid Leukemias

Various cytokines play roles in the process of granulocytic proliferation, differentiation and maturation from hemopoietic stem/progenitor cells and in the functional activation of mature granulocytes. Among these cytokines, the most essential is granulocyte colony-stimulating factor (G-CSF), which is a 19KD glycoprotein composed of 174 amino acids with one o-linked sugar chain. This molecule is known to act almost specifically on the granulocyte lineage by accelerating the production of granulocytes together with the expansion of stem/progenitor cells, stimulating the mobilization of these cells into peripheral blood, and augmenting the various functions of granulocytes. (1) These actions are initiated after the G-CSF molecule binds on the cell surface to its specific receptor (G-CSFR), a member of the receptor family for hemopoietic growth factors. This molecule consists of 813 amino acids that contain a single transmembrane domain. The G-CSF binding to G-CSFR induces a homodimerization of G-CSFR that is required for enforcing the granulocytic proliferation and maturation program. It is suggested that the N-terminal region of its cytoplasmic domain is sufficient to transduce the proliferation signal into cells, while the C-terminal region of G-CSFR plays an essential role in transducing the maturation signal. (2) It has no kinase activity by itself, but the rapid tyrosine phosphorylation of several proteins including the C-terminal region is observed. Recently, many components in the complex intracellular signaling pathway after binding that leads to the various biologic responses have been extensively studied by many investigators. These can be divided into membrane and cytoplasmic phases. Following activation of membrane components such as the activation of a small GTP binding protein via an adapter molecule and a guanine nucleotide exchange factor or other independent signaling molecule, such as JAK2, the various signals enter the cytoplasm by distinct mechanisms such as translocation of the membrane component (STAT1,3) itself into the nucleus. The signals are considered to be transmitted via the sequential activation of cytoplasmic protein kinases, collectively termed protein Ser/Thr kinase cascades, as well. Although it is thought that these phosphorylation cascades eventually activate nuclear and cytosolic regulatory molecules to initiate cellular responses, molecules binding to DNA specific for the granulocyte lineage have not yet been systematically elucidated but are currently the subject of intense investigation. (3,4,5) Meanwhile, myeloid leukemia cells arise by transformation of myeloid stem/progenitor cells. One of the biologic features common to the myeloid leukemia cells may be the frequent expression of the various cytokine receptors including G-CSFR. …