APOPTOSIS OF HEMATOPOIETIC-CELLS BY THE HUMAN GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR MUTANT E21R

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) binds to a high-affinity heterodimeric receptor composed of a specific cu ch ain and a common beta chain (beta(c)), which is shared with the recept ors for interleukins 3 and 5, Hemopoietic cell survival requires GM-CS F binding this high-affinity receptor, We have recently developed the GM-CSF mutant E21R, which selectively binds to the cu chain and behave s as a competitive GM-CSF antagonist, We have now examined the role of E21R on the survival of hemopoietic cells and found that E21R causes apoptosis (programmed cell death) of normal and malignant cells direct ly in the absence of GM-CSF. The direct apoptotic effect of E21R occur red in a dose- and time-dependent manner, Apoptosis by E21R was depend ent on cells expressing the high-affinity GM-CSF receptor and could be blocked by GM-CSF. Significantly, apoptosis of the cells occurred eve n in the presence of the survival factors granulocyte CSF and stem cel l factor but was prevented by engagement of beta(c) with interleukin 3 , The initiation of apoptosis required phosphorylation, transcriptiona l activity, and protein synthesis, These findings support a model wher eby binding of E21R to the cu chain leads to apoptosis, while beta(c) plays an important role in cell survival, This model may be applicable to other multimeric cytokine receptors and offers a novel approach fo r the treatment of human leukemia.