The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate.

Abstract

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.

• Authors: Patrick S Ward, Jay Patel, David R Wise, Omar Abdel-Wahab, Bryson D Bennett, Hilary A Coller, Justin R Cross, Valeria R Fantin, Cyrus V Hedvat, Alexander E Perl, Joshua D Rabinowitz, Martin Carroll, Shinsan M Su, Kim A Sharp, Ross L Levine, Craig B Thompson
• Journal: Cancer cell (Cancer Cell) Vol. 17 Issue 3 Pg. 225-34 (Mar 16 2010) ISSN: 1878-3686 [Electronic] United States
• PMID: 20171147 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright 2010 Elsevier Inc. All rights reserved.

Chemical References

• Glutarates
• Isocitrates
• Ketoglutaric Acids
• alpha-hydroxyglutarate
• isocitric acid
• IDH2 protein, human
• Isocitrate Dehydrogenase
• IDH1 protein, human

Topics

• Cell Proliferation
• Glutarates (metabolism)
• Humans
• Isocitrate Dehydrogenase (chemistry, genetics)
• Isocitrates (chemistry, metabolism)
• Ketoglutaric Acids (metabolism)
• Leukemia, Myeloid, Acute (genetics, metabolism)
• Mitochondria (metabolism)
• Mutation
• Tumor Cells, Cultured