INDUCTION OF THE ERYTHROPOIETIN RECEPTOR GENE AND ACQUISITION OF RESPONSIVENESS TO ERYTHROPOIETIN BY STEM-CELL FACTOR IN HML SE, A HUMAN LEUKEMIC-CELL LINE/

HML/SE is a cytokine-dependent cell line established from childhood ac ute megakaryoblastic leukemia. Granulocyte-macrophage colony-stimulati ng factor or stem cell factor (SCF) alone could stimulate proliferatio n of HML/SE cells, however interleukin-3, interleukin-6, granulocyte c olony-stimulating factor and thrombopoietin could not. Although erythr opoietin (EPO) alone stimulated neither proliferation nor differentiat ion of HML/SE cells, it did stimulate proliferation of HML/SE cells an d production of hemoglobin in the presence of SCF. SCF activated the h uman EPO receptor promoter and induced EPO receptor gene expression. G iven these results, we speculate that HML/SE cells acquired responsive ness to EPO via the EPO receptor induced by SCF. Mutation analysis of putative transcription factor binding sites in the human EPO receptor promoter suggested that Spl, rather than the GATA-1 binding site, cont ributed to the induction of the hEPOR gene. Although it is well docume nted that hematopoietic stem cells and primitive progenitors require b oth an early-acting cytokine and a lineage-specific cytokine to differ entiate to a certain lineage, related mechanisms are not well understo od. HML/SE may serve as an excellent model system to analyze functions of early-acting cytokine SCF and lineage-specific cytokine EPO relate d to proliferation and differentiation of hematopoietic stem cells.