EXPRESSION AND FUNCTIONAL-ANALYSIS OF 2 ISOFORMS OF THE HUMAN GM-CSF RECEPTOR-ALPHA CHAIN IN MYELOID DEVELOPMENT AND LEUKEMIA

The human granulocyte-macrophage colony-stimulating factor receptor (G M-CSFR) alpha chain RNA is alternatively spliced to yield receptor iso forms. Two of these, alpha(1) and alpha(2), differ in their cytoplasmi c domains. Because the GM-CSFR beta chain (beta(c)) is shared with the receptors for interleukins 3 and 5 it is possible that the alpha chai n confers specificity on the GM-CSF response and that the different is oforms might refine this response further. Studies have been directed at determination of the respective biological roles of the alpha(1) an d alpha(2) isoforms. Expression of the isoforms was examined by RNase protection analysis in normal granulocytes and a variety of cell lines of haemopoietic origin, at different stages of differentiation and ac tivation. Expression was also analysed in cells from patients with a v ariety of leukaemic subtypes. Results demonstrated that the relative a bundance of the isoforms was similar in all cell populations examined. The human GM-CSFR alpha(1) or alpha(2) receptors were independently e xpressed in the murine factor-dependent cell line FDC-P1, so that the properties of the receptors could be compared, Cell lines that express ed either receptor could be converted to growth in response to human G M-CSF and assumed a more differentiated phenotype when compared with t he parental cell line, However, the morphology, expression of cell sur face antigens and dose-growth response characteristics did not differ significantly between cells that expressed either the alpha(1) or alph a(2) receptor. These studies demonstrate that the alpha(1) and alpha(2 ) subunits of the GM-CSF receptor are co-ordinately regulated in both normal and malignant haemopoiesis. Furthermore; each receptor is able to deliver both proliferative and differentiative signals to myeloid c ells.