Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1504-1514
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
Caroline A. Evans,
Andrew Pierce,
Sandra A. Winter,
Elaine Spooncer,
Clare M. Heyworth, and
Anthony D. Whetton
From the Department of Biomolecular Sciences, Leukaemia Research Fund
Cellular Development Unit; and CRC Section of Haemopoietic Cell and
Gene Therapeutics, Paterson Institute for Cancer Research, Christie
Hospital NHS Trust, Manchester, United Kingdom.
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 (hGM-CSF) on hematopoietic development were
investigated in hematopoietic progenitor cells. Murine multipotent
factor-dependent cell-Paterson (FDCP)-mix cells, which can
self-renew or differentiate, were transfected with the genes encoding
the unique 
and/or shared 
c human hIL-3 receptor
(hIL-3 R) or hGM-CSF receptor (hGM R) subunits by retroviral gene
transfer. Selective activation of hIL-3 R,c or hGM
R,c 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 subunits act in combination
with the hc to govern developmental decisions. The role
of the subunit in conferring specificity was studied by using a
chimeric receptor composed of the extracellular hIL-3 R and
intracellular hGM R subunit domains. This receptor promoted
differentiation in response to hIL-3. Thus, the subunit cytosolic
domain is an essential component in determining cell fate via specific
signaling events.
