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.
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.
McLemore
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ML
Division of Bone Marrow Transplantation and Stem Cell Biology, Department of Medicine, and Department of Pathology, Washington University Medical School, St. Louis, Missouri 63110, USA.
Poursine-Laurent
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D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004198:Disease Susceptibility; D005260:Female; D005838:Genotype; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009190:Myelodysplastic Syndromes / Q000209:etiology; D009503:Neutropenia / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics
D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor