Identification of functional cooperative mutations of SETD2 in human acute leukemia.
Identification of functional cooperative mutations of SETD2 in human acute leukemia.
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DOI：
10.1038/ng.2894
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发表时间：
2014-03
期刊：
影响因子：
30.8
通讯作者：
Wang, Qian-fei
中科院分区：
文献类型：
--
作者：
Zhu, Xiaofan;He, Fuhong;Zeng, Huimin;Ling, Shaoping;Chen, Aili;Wang, Yaqin;Yan, Xiaomei;Wei, Wei;Pang, Yakun;Cheng, Hui;Hua, Chunlan;Zhang, Yue;Yang, Xuejing;Lu, Xin;Cao, Lihua;Hao, Lingtong;Dong, Lili;Zou, Wei;Wu, Jun;Li, Xia;Zheng, Si;Yan, Jin;Zhou, Jing;Zhang, Lixia;Mi, Shuangli;Wang, Xiaojuan;Zhang, Li;Zou, Yao;Chen, Yumei;Geng, Zhe;Wang, Jianmin;Zhou, Jianfeng;Liu, Xin;Wang, Jianxiang;Yuan, Weiping;Huang, Gang;Cheng, Tao;Wang, Qian-fei
以染色体重排为特征的急性白血病需要额外的分子破坏才能发展成完全的恶性肿瘤，但合作机制仍然难以捉摸。使用全基因组测序的一对单卵双胞胎不一致的MLL（也称为KMT 2A）基因重排白血病，我们确定了一个转化MLL-NRIP 3融合基因和双等位基因突变的SETD 2（编码组蛋白H3 K36甲基转移酶）。此外，在241例急性白血病患者中，SETD 2的功能丧失点突变复发（6.2%），并与多种主要染色体畸变相关。我们观察到在具有SETD 2突变的白血病原始细胞中H3 K36三甲基化（H3 K36 me 3）的整体损失。在存在遗传病变的情况下，SETD 2的下调通过促进白血病干细胞的自我更新潜力而促进白血病发展期间的启动和进展。因此，我们的研究为SETD 2作为一种新的肿瘤抑制因子提供了令人信服的证据。SETD 2-H3 K36 me 3通路的破坏是白血病发展的独特表观遗传机制。
Acute leukemia characterized by chromosomal rearrangements requires additional molecular disruptions to develop into full-blown malignancy, yet the cooperative mechanisms remain elusive. Using whole-genome sequencing of a pair of monozygotic twins discordant for MLL (also called KMT2A) gene-rearranged leukemia, we identified a transforming MLL-NRIP3 fusion gene and biallelic mutations in SETD2 (encoding a histone H3K36 methyltransferase). Moreover, loss-of-function point mutations in SETD2 were recurrent (6.2%) in 241 patients with acute leukemia and were associated with multiple major chromosomal aberrations. We observed a global loss of H3K36 trimethylation (H3K36me3) in leukemic blasts with mutations in SETD2. In the presence of a genetic lesion, downregulation of SETD2 contributed to both initiation and progression during leukemia development by promoting the self-renewal potential of leukemia stem cells. Therefore, our study provides compelling evidence for SETD2 as a new tumor suppressor. Disruption of the SETD2-H3K36me3 pathway is a distinct epigenetic mechanism for leukemia development.
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影响因子：
11.2
作者：
Dondeti VR;Wubbenhorst B;Lal P;Gordan JD;D'Andrea K;Attiyeh EF;Simon MC;Nathanson KL
通讯作者：
Nathanson KL
影响因子：
14.9
作者：
Kanehisa M;Goto S;Sato Y;Furumichi M;Tanabe M
通讯作者：
Tanabe M
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1093/bfgp/elm007
发表时间：
2007-01-01
期刊：
Briefings in Functional Genomics & Proteomics
影响因子：
--
作者：
Angeloni, Debora
通讯作者：
Angeloni, Debora
影响因子：
14.8
作者：
Huang, Da Wei;Sherman, Brad T.;Lempicki, Richard A.
通讯作者：
Lempicki, Richard A.