IDH1 and IDH2 mutations in pediatric acute leukemia.
IDH1 and IDH2 mutations in pediatric acute leukemia.
复制标题
作者：
为了研究异柠檬酸脱氢酶1 （IDH1）和2 （IDH2）突变在儿童急性髓性白血病（AML）和急性淋巴性白血病（ALL）中的频率，我们对515例患者（227例AML和288例ALL）的诊断样本进行了这些基因的测序。体细胞IDH1/IDH2突变在ALL中很少见（N=1），但在AML中更常见，发生率为3.5% (IDH1 N=3和IDH2 N=5)，在核型正常的AML中发生率更高（9.8%）。鉴定的IDH1突变发生在密码子132上，导致精氨酸被半胱氨酸（N=3）或组氨酸（N=1）取代。相比之下，IDH2的突变不影响同源残基，但改变了密码子140，导致精氨酸被谷氨酰胺（N=4）或色氨酸（N=1）取代。IDH2的结构模型表明，密码子140突变破坏了该酶结合底物异柠檬酸盐的能力。因此，重组IDH2 R140Q/W无法将异柠檬酸脱羧为α-酮戊二酸酯（α-KG），而获得了将α-KG还原为R(−)-2-羟基戊二酸酯（2-HG）的新形态活性。对原发性白血病细胞的分析证实，IDH1/IDH2突变的aml中2-HG水平较高。有趣的是，3/5的IDH2突变AMLs具有FLT3激活突变，这提高了这些突变在白血病发生中的协同作用的可能性。
To investigate the frequency of isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations in pediatric acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), we sequenced these genes in diagnostic samples from 515 patients (227 AMLs and 288 ALLs). Somatic IDH1/IDH2 mutations were rare in ALL (N=1), but were more common in AML, occurring in 3.5% (IDH1 N=3 and IDH2 N=5), with the frequency higher in AMLs with a normal karyotype (9.8%). The identified IDH1 mutations occurred in codon 132 resulting in replacement of arginine with either cysteine (N=3) or histidine (N=1). By contrast, mutations in IDH2 did not affect the homologous residue but instead altered codon 140, resulting in replacement of arginine with either glutamine (N=4) or tryptophan (N=1). Structural modeling of IDH2 suggested that codon 140 mutations disrupt the enzyme's ability to bind its substrate isocitrate. Accordingly, recombinant IDH2 R140Q/W were unable to carry out the decarboxylation of isocitrate to α-ketoglutarate (α-KG), but instead gained the neomorphic activity to reduce α-KG to R(−)-2-hydroxyglutarete (2-HG). Analysis of primary leukemic blasts confirmed high levels of 2-HG in AMLs with IDH1/IDH2 mutations. Interestingly, 3/5 AMLs with IDH2 mutations had FLT3 activating mutations, raising the possibility that these mutations cooperate in leukemogenesis.
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
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：
20.3
作者：
Thiede, C;Steudel, C;Illmer, T
通讯作者：
Illmer, T
影响因子：
4.8
作者：
Ceccarelli, C;Grodsky, NB;Bahnson, BJ
通讯作者：
Bahnson, BJ
影响因子：
45.3
作者：
Paschka, Peter;Schlenk, Richard F.;Doehner, Konstanze
通讯作者：
Doehner, Konstanze