(2R,3S)-Dihydroxybutanoic Acid Synthesis as a Novel Metabolic Function of Mutant Isocitrate Dehydrogenase 1 and 2 in Acute Myeloid Leukemia.
(2R,3S)-Dihydroxybutanoic Acid Synthesis as a Novel Metabolic Function of Mutant Isocitrate Dehydrogenase 1 and 2 in Acute Myeloid Leukemia.
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(2R急性髓系白血病中突变型异柠檬酸脱氢酶1和2的新代谢功能--（3S）-二羟基丁酸合成
DOI：
10.3390/cancers12102842
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发表时间：
2020-10-01
期刊：
影响因子：
5.2
通讯作者：
Beyoğlu D
中科院分区：
文献类型：
--
作者：
Idle JR;Seipel K;Bacher U;Pabst T;Beyoğlu D
急性骨髓性白血病（AML）是在癌细胞中突变酶产生的异常代谢物（称为癌代谢物）的影响下发生癌症增殖的几种癌症之一。在AML中，突变的异柠檬酸脱氢酶产生癌代谢物2-羟基戊二酸。我们使用代谢组学技术筛选了有和没有突变型异柠檬酸脱氢酶的AML患者，该技术测量患者血浆中许多不同的代谢物。据观察，另一种代谢产物2，3-二羟基丁酸在异柠檬酸脱氢酶突变患者中产生量更大，与2-羟基戊二酸水平密切相关。此外，2，3-二羟基丁酸是癌症中突变的异柠檬酸脱氢酶存在的更好的指示剂，而不是已知的癌代谢物2-羟基戊二酸。这些发现可能导致2，3-二羟基丁酸酯作为AML中新的肿瘤代谢物的特征，这将使人们更全面地了解这种疾病的病因，并为开发新的治疗药物提供机会。急性髓性白血病（AML）经常在异柠檬酸1（IDH 1）和2（IDH 2）基因中携带突变，导致形成癌代谢物（2 R）-羟基谷氨酸（2 R-HG），对AML增殖和分化具有表观遗传学后果。为了研究广泛的代谢畸变是否可能由AML中的IDH 1和IDH 2突变引起，通过气相色谱-质谱法（GC-MS）对51名AML患者（29名IDH 12野生型（WT）、9名IDH 1 R132、12名IDH 2 R140和1名IDH 2 R172突变）进行血浆代谢组学。在IDH 1/2 WT、IDH 1 R132和IDH 2 R140患者之间观察到明显的代谢差异，其包含22种主要为氨基酸的血浆代谢物。在IDH 1 R132和WT IDH 1/2之间以及IDH 2 R140和WT IDH 1/2之间，仅两种血浆代谢物具有统计学显著性差异（p < 0.0001），特别是（2 R）-羟基谷氨酸（2 R-HG）和苏氨酸代谢物（2 R，3S）-二羟基丁酸（2，3-DHBA）。此外，2 R-HG与血浆中的2，3-DHBA强烈相关（p < 0.0001）。发现1例WT患者存在D-2-羟基戊二酸脱氢酶（D2 HGDH）A426 T失活突变，但这对2 R-HG和2，3-DHBA血浆浓度几乎没有影响。转运蛋白基因SLC 16 A1和SLC 16 A3的表达与2 R-HG的血浆浓度呈弱相关性，但与2，3-DHBA的血浆浓度无关。受试者操作特征（ROC）分析表明，2，3-DHBA是比2 R-HG更好的IDH突变生物标志物（曲线下面积（AUC）0.861; p < 0.0001; 80%特异性; 87.3%灵敏度）。结论：2，3-DHBA和2 R-HG均由突变体IDH 1 R132、IDH 2 R140和IDH 2 R172形成，提示2，3-DHBA在AML发病中可能发挥作用。
Acute myeloid leukemia (AML) is one of several cancers where cancer proliferation occurs under the influence of an aberrant metabolite known as an oncometabolite produced by a mutated enzyme in the cancer cell. In AML, mutant isocitrate dehydrogenases produce the oncometabolite 2-hydroxyglutarate. We screened AML patients with and without mutant isocitrate dehydrogenases by using a technique known as metabolomics, which measures many different metabolites in patient plasma. It was observed that another metabolite, 2,3-dihydroxybutyrate, was produced in larger amounts in patients with mutated isocitrate dehydrogenase and correlated strongly with 2-hydroxyglutarate levels. Moreover, 2,3-dihydroxybutyrate was a better indicator of the presence of mutated isocitrate dehydrogenase in the cancer than the known oncometabolite 2-hydroxyglutarate. These findings may lead to the characterization of 2,3-dihydroxybutyrate as a novel oncometabolite in AML, which would bring a fuller understanding of the etiology of this disease and offer opportunities for the development of novel therapeutic agents. Acute myeloid leukemia (AML) frequently harbors mutations in isocitrate 1 (IDH1) and 2 (IDH2) genes, leading to the formation of the oncometabolite (2R)-hydroxyglutaric acid (2R-HG) with epigenetic consequences for AML proliferation and differentiation. To investigate if broad metabolic aberrations may result from IDH1 and IDH2 mutations in AML, plasma metabolomics was conducted by gas chromatography–mass spectrometry (GC–MS) on 51 AML patients, 29 IDH1/2 wild-type (WT), 9 with IDH1R132, 12 with IDH2R140 and one with IDH2R172 mutations. Distinct metabolic differences were observed between IDH1/2 WT, IDH1R132 and IDH2R140 patients that comprised 22 plasma metabolites that were mainly amino acids. Only two plasma metabolites were statistically significantly different (p < 0.0001) between both IDH1R132 and WT IDH1/2 and IDH2R140 and WT IDH1/2, specifically (2R)-hydroxyglutaric acid (2R-HG) and the threonine metabolite (2R,3S)-dihydroxybutanoic acid (2,3-DHBA). Moreover, 2R-HG correlated strongly (p < 0.0001) with 2,3-DHBA in plasma. One WT patient was discovered to have a D-2-hydroxyglutarate dehydrogenase (D2HGDH) A426T inactivating mutation but this had little influence on 2R-HG and 2,3-DHBA plasma concentrations. Expression of transporter genes SLC16A1 and SLC16A3 displayed a weak correlation with 2R-HG but not 2,3-DHBA plasma concentrations. Receiver operating characteristic (ROC) analysis demonstrated that 2,3-DHBA was a better biomarker for IDH mutation than 2R-HG (Area under the curve (AUC) 0.861; p < 0.0001; 80% specificity; 87.3% sensitivity). It was concluded that 2,3-DHBA and 2R-HG are both formed by mutant IDH1R132, IDH2R140 and IDH2R172, suggesting a potential role of 2,3-DHBA in AML pathogenesis.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
4.8
作者：
Guo C;Pirozzi CJ;Lopez GY;Yan H
通讯作者：
Yan H
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：
Chen, Wen-Lian;Wang, Jing-Han;Jia, Wei
通讯作者：
Jia, Wei
影响因子：
4.2
作者：
Chaumeil, Myriam M.;Radoul, Marina;Ronen, Sabrina M.
通讯作者：
Ronen, Sabrina M.