Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy.
Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy.
复制标题
家族性血小板减少症和血液系统恶性肿瘤中的种系 ETV6 突变。
DOI：
10.1038/ng.3177
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发表时间：
2015-02
期刊：
影响因子：
30.8
通讯作者：
Shimamura A
中科院分区：
文献类型：
--
作者：
Zhang MY;Churpek JE;Keel SB;Walsh T;Lee MK;Loeb KR;Gulsuner S;Pritchard CC;Sanchez-Bonilla M;Delrow JJ;Basom RS;Forouhar M;Gyurkocza B;Schwartz BS;Neistadt B;Marquez R;Mariani CJ;Coats SA;Hofmann I;Lindsley RC;Williams DA;Abkowitz JL;Horwitz MS;King MC;Godley LA;Shimamura A
我们报告了ETV6的胚系错义突变，在三个不相关的家系中分离出显性传播的血小板减少和血液恶性肿瘤，定义了一种新的以血小板减少为特征的遗传性综合征，对各种血液肿瘤易感性。两个变异体p.Arg369Gln和p.Arg399Cys位于高度保守的ETS DNA结合域。第三个变异体p.Pro214Leu位于调节DNA结合的内部连接器域内。这三个氨基酸位点对应于恶性肿瘤中反复发生的体细胞突变的热点。功能研究表明，这些突变消除了DNA结合，改变了亚细胞定位，以显性-负性方式减少了转录抑制，并损害了造血。这些家族遗传学研究确定了ETV6在造血和恶性转化中的核心作用。对血细胞减少症和癌症的生殖系易感性的识别为高危个体的诊断和医疗管理提供了信息。
We report germline missense mutations in ETV6 segregating with the dominant transmission of thrombocytopenia and hematologic malignancy in three unrelated kindreds, defining a new hereditary syndrome featuring thrombocytopenia with susceptibility to diverse hematologic neoplasms. Two variants, p.Arg369Gln and p.Arg399Cys, reside in the highly conserved ETS DNA-binding domain. The third variant, p.Pro214Leu, lies within the internal linker domain, which regulates DNA binding. These three amino acid sites correspond to hotspots for recurrent somatic mutation in malignancies. Functional studies show that the mutations abrogate DNA binding, alter subcellular localization, decrease transcriptional repression in a dominant-negative fashion and impair hematopoiesis. These familial genetic studies identify a central role for ETV6 in hematopoiesis and malignant transformation. The identification of germline predisposition to cytopenias and cancer informs the diagnosis and medical management of at-risk individuals.