title: 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.affiliation: Abramson Cancer Center, Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Ward
authors.forename: Jay
authors.initials: J
authors.lastname: Patel
authors.forename: David R
authors.initials: DR
authors.lastname: Wise
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Bryson D
authors.initials: BD
authors.lastname: Bennett
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Coller
authors.forename: Justin R
authors.initials: JR
authors.lastname: Cross
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Fantin
authors.forename: Cyrus V
authors.initials: CV
authors.lastname: Hedvat
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Perl
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.forename: Martin
authors.initials: M
authors.lastname: Carroll
authors.forename: Shinsan M
authors.initials: SM
authors.lastname: Su
authors.forename: Kim A
authors.initials: KA
authors.lastname: Sharp
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D049109:Cell Proliferation; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000737:chemistry / Q000235:genetics*; D007523:Isocitrates / Q000737:chemistry / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D014407:Tumor Cells, Cultured
chemical_list: D005977:Glutarates; D007523:Isocitrates; D007656:Ketoglutaric Acids; C019417:alpha-hydroxyglutarate; C034219:isocitric acid; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human