The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate.
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.
Ward
Patrick S
PS
Abramson Cancer Center, Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Patel
Jay
J
Wise
David R
DR
Abdel-Wahab
Omar
O
Bennett
Bryson D
BD
Coller
Hilary A
HA
Cross
Justin R
JR
Fantin
Valeria R
VR
Hedvat
Cyrus V
CV
Perl
Alexander E
AE
Rabinowitz
Joshua D
JD
Carroll
Martin
M
Su
Shinsan M
SM
Sharp
Kim A
KA
Levine
Ross L
RL
Thompson
Craig B
CB
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
D005977:Glutarates; D007523:Isocitrates; D007656:Ketoglutaric Acids; C019417:alpha-hydroxyglutarate; C034219:isocitric acid; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human