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Blood. 1999 Jan 15;93(2):440-6.

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

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  • 1Molecular, 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.

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.

PMID:
9885205
[PubMed - indexed for MEDLINE]
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