文章：

乙醇胺激酶1（ETNK1）基因在伴有嗜酸性粒细胞增多症的系统性肥大细胞增多症及慢性粒单核细胞白血病中的新型复发性突变

Novel recurrent mutations in ethanolamine kinase 1 (ETNK1) gene in systemic mastocytosis with eosinophilia and chronic myelomonocytic leukemia

原文发布日期：2015-01-23

DOI: 10.1038/bcj.2014.94

类型: Original Article

开放获取: 是

英文摘要：

Although KITD816V occurs universally in adult systemic mastocytosis (SM), the clinical heterogeneity of SM suggests presence of additional phenotype-patterning mutations. Because up to 25% of SM patients have KITD816V-positive eosinophilia, we undertook whole-exome sequencing in a patient with aggressive SM with eosinophilia to identify novel genetic alterations. We conducted sequencing of purified eosinophils (clone/tumor sample), with T-lymphocytes as the matched control/non-tumor sample. In addition to KITD816V, we identified a somatic missense mutation in ethanolamine kinase 1 (ETNK1N244S) that was not present in 50 healthy controls. Targeted resequencing of 290 patients showed ETNK1 mutations to be distributed as follows: (i) SM (n=82; 6% mutated); (ii) chronic myelomonocytic leukemia (CMML; n=29; 14% mutated); (iii) idiopathic hypereosinophilia (n=137; <1% mutated); (iv) primary myelofibrosis (n=32; 0% mutated); and (v) others (n=10; 0% mutated). Of the 82 SM cases, 25 had significant eosinophilia; of these 20% carried ETNK1 mutations. The ten mutations (N244S=6, N244T=1, N244K=1, G245A=2) targeted two contiguous amino acids in the ETNK1 kinase domain, and are predicted to be functionally disruptive. In summary, we identified novel somatic missense ETNK1 mutations that were most frequent in SM with eosinophilia and CMML; this suggests a potential pathogenetic role for dysregulated cytidine diphosphate-ethanolamine pathway metabolites in these diseases.

摘要翻译： 

尽管KITD816V突变在成人系统性肥大细胞增多症（SM）中普遍存在，但该疾病的临床异质性提示还存在其他表型模式突变。鉴于高达25%的SM患者存在KITD816V阳性嗜酸性粒细胞增多，我们对一例伴有嗜酸性粒细胞增生的侵袭性SM患者进行全外显子组测序以识别新的遗传变异。我们对纯化的嗜酸性粒细胞（克隆/肿瘤样本）进行测序，并以T淋巴细胞作为匹配对照/非肿瘤样本。除KITD816V外，我们还在乙醇胺激酶1（ETNK1N244S）中发现了一个体细胞错义突变，该突变在50名健康对照者中均未出现。对290例患者的靶向重测序显示ETNK1突变分布如下：（i）SM（n=82；6%存在突变）；（ii）慢性粒-单核细胞白血病（CMML；n=29；14%存在突变）；（iii）特发性高嗜酸性粒细胞综合征（n=137；<1%存在突变）；（iv）原发性骨髓纤维化（n=32；0%存在突变）；（v）其他疾病（n=10；0%存在突变）。在82例SM病例中，25例存在显著嗜酸性粒细胞增多，其中20%携带ETNK1突变。这10个突变（N244S=6、N244T=1、N244K=1、G245A=2）靶向ETNK1激酶域中两个相邻氨基酸，预计会破坏蛋白功能。总之，我们发现了新型ETNK1体细胞错义突变，在伴嗜酸性粒细胞增多的SM和CMML中最为常见，这表明胞苷二磷酸-乙醇胺通路代谢紊乱可能在这些疾病中发挥致病作用。

原文链接：

Novel recurrent mutations in ethanolamine kinase 1 (ETNK1) gene in systemic mastocytosis with eosinophilia and chronic myelomonocytic leukemia