title: Deletion of a critical internalization domain in the G-CSFR in acute myelogenous leukemia preceded by severe congenital neutropenia.
abstract: 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.
authors.affiliation: Molecular, Cellular, and Developmental Biology Program, Bone Marrow Transplantation Program, The Ohio State University, Arthur G. James Cancer Hospital and Research Institute, Columbus, OH 43210, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Hunter
authors.forename: B R
authors.initials: BR
authors.lastname: Avalos
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D019556:COS Cells; D002455:Cell Division; D004591:Electrophoresis, Polyacrylamide Gel; D017353:Gene Deletion; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007163:Immunosorbent Techniques; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics; D010641:Phenotype; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor