PLENARY PAPER Activation of Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-3 Receptor Subunits in a Multipotential Hematopoietic Progenitor Cell Line Leads to Differential Effects on Development

Activation of specific cytokine receptors promotes survival and proliferation of hematopoietic progenitor cells but their role in the control of differentiation is unclear. To address this issue, the effects of human interleukin-3 (hIL-3) and human granulocyte-macrophage colony-stimulating factor (hGMCSF) on hematopoietic development were investigated in hematopoietic progenitor cells. Murine multipotent factordependent cell-Paterson (FDCP)-mix cells, which can selfrenew or differentiate, were transfected with the genes encoding the unique a and/or shared bc human hIL-3 receptor (hIL-3 R) or hGM-CSF receptor (hGM R) subunits by retroviral gene transfer. Selective activation of hIL-3 Ra,bc or hGM Ra,bc transfects by hIL-3 and hGM-CSF promoted self-renewal and myeloid differentiation, respectively, over a range of cytokine (0.1 to 100 ng/mL) concentrations. These qualitatively distinct developmental outcomes were associated with different patterns of protein tyrosine phosphorylation and, thus, differential signaling pathway activation. The cell lines generated provide a model to investigate molecular events underlying self-renewal and differentiation and indicate that the a subunits act in combination with the hbc to govern developmental decisions. The role of the a subunit in conferring specificity was studied by using a chimeric receptor composed of the extracellular hIL-3 Ra and intracellular hGM Ra subunit domains. This receptor promoted differentiation in response to hIL-3. Thus, the a subunit cytosolic domain is an essential component in determining cell fate via specific signaling events. r 1999 by The American Society of Hematology.