文章：

TET2功能降低导致小鼠发生具有滤泡辅助T细胞样特征的T细胞淋巴瘤

Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice

原文发布日期：2014-12-12

DOI: 10.1038/bcj.2014.83

类型: Original Article

开放获取: 是

英文摘要：

TET2 (Ten Eleven Translocation 2) is a dioxygenase that converts methylcytosine (mC) to hydroxymethylcytosine (hmC). TET2 loss-of-function mutations are highly frequent in subtypes of T-cell lymphoma that harbor follicular helper T (Tfh)-cell-like features, such as angioimmunoblastic T-cell lymphoma (30–83%) or peripheral T-cell lymphoma, not otherwise specified (10–49%), as well as myeloid malignancies. Here, we show that middle-aged Tet2 knockdown (Tet2gt/gt) mice exhibit Tfh-like cell overproduction in the spleen compared with control mice. The Tet2 knockdown mice eventually develop T-cell lymphoma with Tfh-like features after a long latency (median 67 weeks). Transcriptome analysis revealed that these lymphoma cells had Tfh-like gene expression patterns when compared with splenic CD4-positive cells of wild-type mice. The lymphoma cells showed lower hmC densities around the transcription start site (TSS) and higher mC densities at the regions of the TSS, gene body and CpG islands. These epigenetic changes, seen in Tet2 insufficiency-triggered lymphoma, possibly contributed to predated outgrowth of Tfh-like cells and subsequent lymphomagenesis. The mouse model described here suggests that TET2 mutations play a major role in the development of T-cell lymphoma with Tfh-like features in humans.

摘要翻译： 

TET2（十ー易位2）是一种双加氧酶，可将甲基胞嘧啶（mC）转化为羟甲基胞嘧啶（hmC）。TET2功能缺失突变在具有滤泡辅助T细胞（Tfh）样特征的T细胞淋巴瘤亚型中极为常见，例如血管免疫母细胞性T细胞淋巴瘤（30-83%）或非特指型外周T细胞淋巴瘤（10-49%），在髓系恶性肿瘤中亦如此。本研究发现，与对照组相比，中年Tet2基因敲除（Tet2gt/gt）小鼠脾脏中表现出Tfh样细胞过度增殖。经过长潜伏期（中位时间67周）后，这些Tet2敲除小鼠最终发展出具有Tfh样特征的T细胞淋巴瘤。转录组分析显示，与野生型小鼠脾脏CD4阳性细胞相比，这些淋巴瘤细胞具有Tfh样基因表达模式。淋巴瘤细胞在转录起始位点（TSS）周围呈现较低的hmC密度，而在TSS区域、基因体和CpG岛区域呈现较高的mC密度。这些表观遗传学改变可见于Tet2功能不足引发的淋巴瘤，可能促进了Tfh样细胞的早期过度生长及后续淋巴瘤生成。本研究描述的小鼠模型表明，TET2突变在人类具有Tfh样特征的T细胞淋巴瘤发展中起主要作用。

原文链接：

Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice