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 (SCN) who develop acute myelogenous leukemia (AML). These mutations affect one allele and result in hyperproliferative responses to G-CSF, presumably through a dominant-negative mechanism. Here we show that a critical domain in the G-CSFR that mediates ligand internalization is deleted in mutant G-CSFR forms from patients with SCN/AML. Deletion of this domain results in impaired ligand internalization, defective receptor downmodulation, and enhanced growth signaling. These results explain the molecular basis for G-CSFR mutations in the pathogenesis of the dominant-negative phenotype and hypersensitivity to G-CSF in SCN/AML.