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
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
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DOI：
10.1172/jci3216
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发表时间：
1998-08-01
影响因子：
15.9
通讯作者：
Link, DC
中科院分区：
文献类型：
--
作者：
McLemore, ML;Poursine-Laurent, J;Link, DC
粒细胞集落刺激因子受体（G-CSFR）突变在严重先天性中性粒细胞减少症（SCN）的发病机制和随后发展为急性髓性白血病（AML）中的作用是有争议的。已经产生了携带G-CSFR靶向突变的小鼠，该突变复制了在SCN和AML患者中发现的突变。突变的G-CSFR等位基因以骨髓特异性的方式表达，其水平与野生型等位基因相当。杂合或纯合突变小鼠的循环中性粒细胞水平正常，没有证据表明髓样成熟阻滞，表明静息时的颗粒生成正常。然而，在对G-CSF治疗的反应中，这些小鼠的循环中性粒细胞水平显著增加了两倍。这种影响似乎是由于骨髓中对g - csf有反应的祖细胞的绝对数量和它们对C-CSF的反应的增殖增加，中性粒细胞的产生增加。此外，突变中性粒细胞的体外存活和g - csf依赖性的凋亡抑制是正常的。尽管有证据表明对G-CSF有超增殖反应，但迄今为止尚未发现AML病例，这些数据表明，在SCN患者中发现的G-CSFR突变不足以在小鼠中诱导SCN表型或AML。
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 wildtype 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 C-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.