Growth regulation of malignant clonogenic cells in acute myeloid leukemia

Myeloid leukemic progenitor cells proliferate in vitro in response to a variety of humoral factors, the most prominent among these being granulocyte-macrophage colony-stimulating factor (GM-CSF). The mechanism by which GM-CSF transduces its proliferative signal in acute myeloid leukemia has been extensively investigated over the past year. It is now known that the GM-CSF belongs to a new family of hematopoietic growth factor binding proteins which are characterized by a relatively short intracytoplasmic domain that lacks a tyrosine kinase sequence. Nevertheless, studies performed using GM-CSF-dependent leukemic cell lines demonstrate the appearance of several new phosphotyrosine species after GM-CSF exposure, suggesting that receptor activation is directly or indirectly linked to tyrosine kinase stimulation. Apart from the basic biology of GM-CSF-induced signal transduction, the ability of this factor to enhance the S-phase fraction of myeloid leukemia blasts may have important therapeutic implications. Clinical trials are currently being conducted in an attempt to determine whether GM-CSF is able to overcome kinetic resistance of leukemic myeloblasts to cell cycle-specific agents such as cytarabine in the treatment of patients with acute myeloid leukemia.