TET1 is a tumor suppressor of hematopoietic malignancy.
TET1 is a tumor suppressor of hematopoietic malignancy.
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DOI：
10.1038/ni.3148
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发表时间：
2015-06
影响因子：
30.5
通讯作者：
Aifantis I
中科院分区：
文献类型：
--
作者：
Cimmino L;Dawlaty MM;Ndiaye-Lobry D;Yap YS;Bakogianni S;Yu Y;Bhattacharyya S;Shaknovich R;Geng H;Lobry C;Mullenders J;King B;Trimarchi T;Aranda-Orgilles B;Liu C;Shen S;Verma AK;Jaenisch R;Aifantis I
TET 甲基胞嘧啶双加氧酶 1 (TET1) 酶是胚胎干细胞中 5-羟甲基胞嘧啶 (5hmC) 的重要调节因子。许多肿瘤中 TET 蛋白表达的减少和 5hmC 的丢失表明这种表观遗传修饰的维持发挥着关键作用。在这里，我们发现 Tet1 的缺失促进了小鼠 B 细胞淋巴瘤的发展。 Tet1 是维持 5hmC 正常含量、防止 DNA 高甲基化以及调节 B 细胞谱系、染色体维护和 DNA 修复基因所必需的。 Tet1 缺陷肿瘤的全外显子组测序揭示了非霍奇金 B 细胞淋巴瘤中常见的突变，其中 TET1 高度甲基化且转录沉默。这些发现提供了 TET1 作为造血系统恶性肿瘤的肿瘤抑制因子的体内证据。
The TET methylcytosine dioxygenase 1 (TET1) enzyme is an important regulator of 5-hydroxymethylcytosine (5hmC) in embryonic stem cells. Decreased expression of TET proteins and loss of 5hmC in many tumors suggests a critical role for the maintenance of this epigenetic modification. Here we show that deletion of Tet1 promoted the development of B cell lymphoma in mice. Tet1 was required for maintaining normal content of 5hmC, preventing DNA hypermethylation and in the regulation of B cell lineage, chromosome maintenance and DNA repair genes. Whole-exome sequencing of Tet1-deficient tumors revealed mutations frequently found in Non-Hodgkin B cell lymphoma, where TET1 was hypermethylated and transcriptionally silenced. These findings provide in vivo evidence of TET1 function as a tumor suppressor of hematopoietic malignancy.