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

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

Research output: Contribution to journalArticlepeer-review

1232 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)225-234
Number of pages10
JournalCancer Cell
Volume17
Issue number3
DOIs
StatePublished - Mar 16 2010

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

Keywords

  • CELLCYCLE
  • DNA
  • HUMDISEASE

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