The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate

被引：1671

作者：

Ward, Patrick S. ^{[1
]}

Patel, Jay ^{[4
]}

Wise, David R. ^{[1
]}

Abdel-Wahab, Omar ^{[4
]}

Bennett, Bryson D. ^{[5
]}

Coller, Hilary A. ^{[6
]}

Cross, Justin R. ^{[1
]}

Fantin, Valeria R. ^{[7
]}

Hedvat, Cyrus V. ^{[3
]}

Perl, Alexander E. ^{[1
]}

Rabinowitz, Joshua D. ^{[5
]}

Carroll, Martin ^{[1
]}

Su, Shinsan M. ^{[7
]}

Sharp, Kim A. ^{[2
]}

Levine, Ross L. ^{[4
]}

Thompson, Craig B. ^{[1
]}

机构：

[1] Univ Penn, Dept Med, Div Hematol & Oncol, Abramson Canc Ctr, Philadelphia, PA 19104 USA

[2] Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA

[3] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[4] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[5] Princeton Univ, Dept Chem & Integrat Genom, Princeton, NJ 08544 USA

[6] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA

[7] Agios Pharmaceut, Cambridge, MA 02139 USA

来源：

CANCER CELL | 2010年 / 17卷 / 03期

关键词：

QUANTITATION; METABOLITES; GLYCOLYSIS; ISOCITRATE; ACIDS;

D O I：

10.1016/j.ccr.2010.01.020

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The somatic mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) observed in gliomas can lead to the production of 2-hydroxyglutarate (2HG). Here, we report that tumor 2HG is elevated in a high percentage of patients with cytogenetically normal acute myeloid leukemia (AML). Surprisingly, less than half of cases with elevated 2HG possessed IDH1 mutations. The remaining cases with elevated 2HG had mutations in IDH2, the mitochondrial homolog of IDH1. These data demonstrate that a shared feature of all cancer-associated IDH mutations is production of the oncometabolite 2HG. Furthermore, AML patients with IDH mutations display a significantly reduced number of other well characterized AML-associated mutations and/or associated chromosomal abnormalities, potentially implicating IDH mutation in a distinct mechanism of AML pathogenesis.

引用

页码：225 / 234

页数：10

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