Mice expressing a neutrophil elastase mutation derived from patients with severe congenital neutropenia have normal granulopoiesis
Mice expressing a neutrophil elastase mutation derived from patients with severe congenital neutropenia have normal granulopoiesis
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DOI：
10.1182/blood-2002-05-1372
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发表时间：
2002-11-01
期刊：
影响因子：
20.3
通讯作者：
Link, DC
中科院分区：
文献类型：
--
作者：
Grenda, DS;Johnson, SE;Link, DC
严重先天性中性粒细胞减少症（SCN）是一种以粒细胞分化的孤立性阻滞为特征的综合征，其发展为急性髓细胞白血病（AML）的风险增加。最近的研究表明，大多数SCN和周期性中性粒细胞减少症（一种以循环中性粒细胞数量周期性波动为特征的相关疾病）患者在编码中性粒细胞弹性蛋白酶（NE）的ELA 2基因中存在杂合种系突变。为了检验这些突变是SCN病因的假设，我们产生了携带其Ela2基因的靶向突变（“V72M”）的转基因小鼠，其再现了在2名不相关的SCN患者中发现的突变，其中一名患者发展为AML。证实了突变NE mRNA和酶活性蛋白的表达。V72M等位基因杂合子和纯合子小鼠的循环中性粒细胞数量正常，骨髓中未观察到髓样前体细胞蓄积。系列血液分析没有发现任何主要造血谱系的循环证据。细胞因子剥夺后的凋亡率在野生型和突变型中性粒细胞中相似，髓系祖细胞的频率和细胞因子反应性也相似。通过环磷酰胺诱导的骨髓抑制后中性粒细胞恢复测量的应激粒细胞生成反应正常。为了确定MM NE的致白血病潜力，建立了肿瘤观察。迄今为止，尚未发现白血病病例。总的来说，这些数据表明V72M NE的表达不足以在小鼠中诱导SCN表型或白血病。(C)2002年，美国血液学会。
Severe congenital neutropenia (SCN) is a syndrome characterized by an isolated block in granulocytic differentiation and an increased risk of developing acute myeloid leukemia (AML). Recent studies have demonstrated that the majority of patients with SCN and cyclic neutropenia, a related disorder characterized by periodic oscillations in the number of circulating neutrophils, have heterozygous germline mutations in the ELA2gene encoding neutrophil elastase (NE). To test the hypothesis that these mutations are causative for SCN, We generated transgenic mice carrying a targeted mutation of their Ela2 gene ("V72M") reproducing a mutation found in 2 unrelated patients wit h SCN, one of whom developed AML. Expression of mutant NE mRNA and enzymatically active protein was confirmed.. Mice heterozygous and homozygous for the V72M allele have normal numbers of circulating neutrophils, and no accumulation of myeloid precursors in the bone marrow was observed. Serial blood analysis found no evidence of cycling in any of the major hematopoietic lineages. Rates of apoptosis following cytokine deprivation were similar in wild-type and mutant neutrophils, as were the frequency and cytokine responsiveness of myeloid progenitors. The stress granulopoiesis response, as measured by neutrophil recovery after cyclophosphamide-induced myelosuppression, was normal. To define the leukemogenic potential of MM NE, a tumor watch was established. To date, no cases of leukemia have been detected. Collectively, these data suggest that expression of V72M NE is not sufficient to induce an SCN phenotype or leukemia in mice. (C) 2002 by The American Society of Hematology.