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.
AUTOR(ES)
McLemore, M L
RESUMO
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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=508908Documentos Relacionados
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