Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice.
Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice.
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DOI：
10.1038/bcj.2014.83
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发表时间：
2014-12-12
影响因子：
12.8
通讯作者：
Chiba S
中科院分区：
文献类型：
--
作者：
Muto H;Sakata-Yanagimoto M;Nagae G;Shiozawa Y;Miyake Y;Yoshida K;Enami T;Kamada Y;Kato T;Uchida K;Nanmoku T;Obara N;Suzukawa K;Sanada M;Nakamura N;Aburatani H;Ogawa S;Chiba S
TET 2（Ten Eleven Translocation 2）是将甲基胞嘧啶（mC）转化为羟甲基胞嘧啶（hmC）的双加氧酶。TET 2功能丧失突变在具有滤泡辅助性T（Tfh）细胞样特征的T细胞淋巴瘤亚型中非常常见，如血管免疫母细胞性T细胞淋巴瘤（30-83%）或未另行说明的外周T细胞淋巴瘤（10-49%）以及骨髓恶性肿瘤。在这里，我们表明，中年Tet 2敲低（Tet 2gt/gt）小鼠表现出Tfh样细胞在脾脏中的过度生产与对照小鼠相比。Tet 2敲除小鼠最终在长潜伏期（中位数67周）后发展出具有Tfh样特征的T细胞淋巴瘤。转录组分析显示，这些淋巴瘤细胞与野生型小鼠脾CD 4阳性细胞相比，具有Tfh样基因表达模式。淋巴瘤细胞在转录起始位点（TSS）周围表现出较低的hmC密度，而在TSS、基因体和CpG岛区域表现出较高的mC密度。这些表观遗传变化在Tet 2不足触发的淋巴瘤中观察到，可能导致Tfh样细胞的提前生长和随后的淋巴瘤发生。这里描述的小鼠模型表明TET 2突变在人类具有Tfh样特征的T细胞淋巴瘤的发展中起主要作用。
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.
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影响因子：
30.8
作者：
Busque L;Patel JP;Figueroa ME;Vasanthakumar A;Provost S;Hamilou Z;Mollica L;Li J;Viale A;Heguy A;Hassimi M;Socci N;Bhatt PK;Gonen M;Mason CE;Melnick A;Godley LA;Brennan CW;Abdel-Wahab O;Levine RL
通讯作者：
Levine RL
影响因子：
3.7
作者：
Auguste T;Travert M;Tarte K;Amé-Thomas P;Artchounin C;Martin-Garcia N;de Reynies A;de Leval L;Gaulard P;Delfau-Larue MH
通讯作者：
Delfau-Larue MH
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
30.8
作者：
Langemeijer, Saskia M. C.;Kuiper, Roland P.;Jansen, Joop H.
通讯作者：
Jansen, Joop H.
影响因子：
20.3
作者：
de Leval, Laurence;Rickman, David S.;Gaulard, Philippe
通讯作者：
Gaulard, Philippe