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.
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.
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McLemore
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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