Induction of sarcomas by mutant IDH2.
Induction of sarcomas by mutant IDH2.
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DOI：
10.1101/gad.226753.113
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发表时间：
2013-09-15
影响因子：
10.5
通讯作者：
Thompson CB
中科院分区：
文献类型：
--
作者：
Lu C;Venneti S;Akalin A;Fang F;Ward PS;Dematteo RG;Intlekofer AM;Chen C;Ye J;Hameed M;Nafa K;Agaram NP;Cross JR;Khanin R;Mason CE;Healey JH;Lowe SW;Schwartz GK;Melnick A;Thompson CB
大多数软骨肉瘤患者在IDH 1或IDH 2中表现出功能获得性突变。Lu等人发现IDH突变与软骨肉瘤活检组织中CpG岛的DNA超甲基化相关。高甲基化区域富含与干细胞维持/分化和谱系特化有关的基因。在小鼠间充质祖细胞中，突变IDH 2导致DNA高甲基化和分化障碍，这可以通过DNA低甲基化剂逆转。突变IDH 2也在体内产生未分化的肉瘤。这项工作表明，neomorphic IDH 2突变可以在间充质细胞中致癌。超过50%的软骨肉瘤患者表现出异柠檬酸脱氢酶1（IDH 1）或IDH 2的功能获得性突变。在这项研究中，我们对软骨肉瘤活检组织进行了全基因组CpG甲基化测序，发现IDH突变与CpG岛的DNA超甲基化相关，而与其他基因组区域无关。CpG岛高甲基化区域富含与干细胞维持/分化和谱系特化有关的基因。在小鼠10 T1/2间充质祖细胞中，突变IDH 2的表达导致DNA高甲基化和分化障碍，这可以通过DNA低甲基化剂治疗来逆转。引入突变IDH 2也诱导接触抑制的丧失并在体内产生未分化的肉瘤。突变IDH 2的致癌潜力与产生2-羟基戊二酸的能力相关。总之，这些数据表明，新形态IDH 2突变可以在间充质细胞中致癌。
Most chondrosarcoma patients exhibit gain-of-function mutations in either IDH1 or IDH2. Lu et al. found that IDH mutations were associated with DNA hypermethylation at CpG islands in chondrosarcoma biopsies. Regions of hypermethylation were enriched for genes implicated in stem cell maintenance/differentiation and lineage specification. In murine mesenchymal progenitor cells, mutant IDH2 led to DNA hypermethylation and impairment in differentiation, which could be reversed by DNA-hypomethylating agents. Mutant IDH2 also generated undifferentiated sarcomas in vivo. This work demonstrates that neomorphic IDH2 mutations can be oncogenic in mesenchymal cells. More than 50% of patients with chondrosarcomas exhibit gain-of-function mutations in either isocitrate dehydrogenase 1 (IDH1) or IDH2. In this study, we performed genome-wide CpG methylation sequencing of chondrosarcoma biopsies and found that IDH mutations were associated with DNA hypermethylation at CpG islands but not other genomic regions. Regions of CpG island hypermethylation were enriched for genes implicated in stem cell maintenance/differentiation and lineage specification. In murine 10T1/2 mesenchymal progenitor cells, expression of mutant IDH2 led to DNA hypermethylation and an impairment in differentiation that could be reversed by treatment with DNA-hypomethylating agents. Introduction of mutant IDH2 also induced loss of contact inhibition and generated undifferentiated sarcomas in vivo. The oncogenic potential of mutant IDH2 correlated with the ability to produce 2-hydroxyglutarate. Together, these data demonstrate that neomorphic IDH2 mutations can be oncogenic in mesenchymal cells.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
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：
10.5
作者：
Sasaki, Masato;Knobbe, Christiane B.;Mak, Tak Wah
通讯作者：
Mak, Tak Wah
影响因子：
12.3
作者：
Akalin A;Kormaksson M;Li S;Garrett-Bakelman FE;Figueroa ME;Melnick A;Mason CE
通讯作者：
Mason CE