Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation.
Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation.
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DOI：
10.1016/j.ccr.2010.11.015
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发表时间：
2010-12-14
期刊：
影响因子：
50.3
通讯作者：
Melnick A
中科院分区：
文献类型：
--
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
癌症相关的IDH突变的特征在于新变体酶活性和所得的2羟基戊二酸（2 HG）产生。一个大型AML患者队列的突变和表观遗传学分析显示，IDH 1/2突变AML显示出全局DNA超甲基化和特异性超甲基化特征。此外，细胞中产生2 HG的IDH等位基因的表达诱导了整体DNA超甲基化。在AML队列中，IDH 1/2突变与α-酮戊二酸依赖性酶TET 2突变相互排斥，TET 2功能丧失突变与IDH 1/2突变体相似的表观遗传缺陷相关。与这些遗传和表观遗传数据一致，IDH突变体的表达损害了细胞中的TET 2催化功能。最后，突变IDH 1/2或Tet 2缺失的表达损害造血分化并增加干/祖细胞标志物表达，表明共同的促白血病作用。
Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2 hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large AML patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the α-ketoglutarate-dependent enzyme TET2, and TET2 loss-of-function mutations associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem/progenitor cell marker expression, suggesting a shared proleukemogenic effect.
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影响因子：
12.7
作者：
Hartmann, Christian;Meyer, Jochen;von Deimling, Andreas
通讯作者：
von Deimling, Andreas
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
50.3
作者：
Ward PS;Patel J;Wise DR;Abdel-Wahab O;Bennett BD;Coller HA;Cross JR;Fantin VR;Hedvat CV;Perl AE;Rabinowitz JD;Carroll M;Su SM;Sharp KA;Levine RL;Thompson CB
通讯作者：
Thompson CB
影响因子：
16
作者：
Fujiwara T;O'Geen H;Keles S;Blahnik K;Linnemann AK;Kang YA;Choi K;Farnham PJ;Bresnick EH
通讯作者：
Bresnick EH
影响因子：
45.3
作者：
Wagner, Katharina;Damm, Frederik;Krauter, Juergen
通讯作者：
Krauter, Juergen