Deletion of a critical internalization domain in the G-CSFR in acute myelogenous leukemia preceded by severe congenital neutropenia

Acquired mutations in the granulocyte colony-stimulating factor receptor (G -CSFR) occur in a subset of patients with severe congenital neutropenia (SC N) who develop acute myelogenous leukemia (AML). These mutations affect one allele and result in hyperproliferative responses to G-CSF, presumably thr ough a dominant-negative mechanism. Here we show that a critical domain in the G-CSFR that mediates (ligand internalization is deleted in mutant G-CSF R forms from patients with SCN/AML. Deletion of this domain results in impa ired ligand internalization, defective receptor downmodulation, and enhance d growth signaling. These results explain the molecular basis for G-CSFR mu tations in the pathogenesis of the dominant-negative phenotype and hypersen sitivity to G-CSF in SCN/AML. (C) 1999 by The American Society of Hematolog y.