GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR RECEPTORS ALTER THEIR BINDING CHARACTERISTICS DURING MYELOID MATURATION THROUGH UP-REGULATION OF THE AFFINITY CONVERTING BETA-SUBUNIT (KH97)

Acute myeloid leukemia blasts express dual affinity (high and low) gra nulocyte-macrophage colony-stimulating factor (GM-CSF) binding, and th e high affinity GM-CSF binding is counteracted by excess interteukin-3 (IL-3). Neutrophils express a single class of GM-CSF-R with intermedi ate affinity that lack IL-3 cross-reactivity. Here we demonstrate the differentiation associated changes of GM-CSF binding characteristics i n three models representative of different stages of myeloid maturatio n. We find that high affinity GM-CSF binding is converted into interme diate affinity binding, which still cross-reacts with IL-3, beyond the stage of promyelocytes. During terminal maturation towards neutrophil s, IL-3 cross-reactivity is gradually lost. We sought to determine the mechanism underlying the affinity conversion of the GM-CSF-R. Norther n and reverse transcriptase-polymerase chain reaction analysis of GM-C SF-Ralpha and -beta(c) (KH97) transcripts did not provide indications for the involvement of GM-CSF-R splice variants in the formation of th e intermediate affinity GM-CSFR complex. In COS-cell transfectants wit h increasing amounts of beta(c) in the presence of a fixed number of G M-CSF-Ralpha chains, the high affinity GM-CSF binding converted into i ntermediate affinity GM-CSF binding. These results are discussed in vi ew of the concept that increasing expression of beta(c) subunits may c ause alternative oligomerization of the GM-CSF-Ralpha and -beta(c) sub units resulting in the formation of intermediate rather than high affi nity GM-CSFRalpha.beta(c) complexes.