Increased granulocyte colony-stimulating factor responsiveness but normal resting granulopoiesis in mice carrying a targeted granulocyte colony- stimulating factor receptor mutation derived from a patient with severe congenital neutropenia

Morgan L. McLemore, Jennifer Poursine-Laurent, Daniel C. Link

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

Abstract

The role of mutations of the granulocyte colony-stimulating factor receptor (G-CSFR) in the pathogenesis of severe congenital neutropenia (SCN) and the subsequent development of acute myeloid leukemia (AML) is controversial. Mice carrying a targeted mutation of their G-CSFR that reproduces the mutation found in a patient with SCN and AML have been generated. The mutant G-CSFR allele is expressed in a myeloid-specific fashion at levels comparable to the wild-type allele. Mice heterozygous or homozygous for this mutation have normal levels of circulating neutrophils and no evidence for a block in myeloid maturation, indicating that resting granulopoiesis is normal. However, in response to G-CSF treatment, these mice demonstrate a significantly greater fold increase in the level of circulating neutrophils. This effect appears to be due to increased neutrophil production as the absolute number of G-CSF-responsive progenitors in the bone marrow and their proliferation in response to G-CSF is increased. Furthermore, the in vitro survival and G-CSF-dependent suppression of apoptosis of mutant neutrophils are normal. Despite this evidence for a hyperproliferative response to G-CSF, no cases of AML have been detected to date. These data demonstrate that the G-CSFR mutation found in patients with SCN is not sufficient to induce an SCN phenotype or AML in mice.

Original languageEnglish
Pages (from-to)483-492
Number of pages10
JournalJournal of Clinical Investigation
Volume102
Issue number3
DOIs
StatePublished - Aug 1 1998

Keywords

  • Leukemia
  • Mice, transgenic
  • Neutropenia/congenital
  • Point mutations
  • Receptors, granulocytic colonystimulating factor

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