Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations.
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), are present in most gliomas and secondary glioblastomas, but are rare in other neoplasms. IDH1/2 mutations are heterozygous, and affect a single arginine residue. Recently, IDH1 mutations were identified in 8% of acute myelogenous leukemia (AML) patients. A glioma study revealed that IDH1 mutations cause a gain-of-function, resulting in the production and accumulation of 2-hydroxyglutarate (2-HG). Genotyping of 145 AML biopsies identified 11 IDH1 R132 mutant samples. Liquid chromatography-mass spectrometry metabolite screening revealed increased 2-HG levels in IDH1 R132 mutant cells and sera, and uncovered two IDH2 R172K mutations. IDH1/2 mutations were associated with normal karyotypes. Recombinant IDH1 R132C and IDH2 R172K proteins catalyze the novel nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of alpha-ketoglutarate (alpha-KG) to 2-HG. The IDH1 R132C mutation commonly found in AML reduces the affinity for isocitrate, and increases the affinity for NADPH and alpha-KG. This prevents the oxidative decarboxylation of isocitrate to alpha-KG, and facilitates the conversion of alpha-KG to 2-HG. IDH1/2 mutations confer an enzymatic gain of function that dramatically increases 2-HG in AML. This provides an explanation for the heterozygous acquisition of these mutations during tumorigenesis. 2-HG is a tractable metabolic biomarker of mutant IDH1/2 enzyme activity.
Agios Pharmaceuticals Incorporated, Cambridge, MA 02139, USA.
Stefan
S
Gross
Rob A
RA
Cairns
Mark D
MD
Minden
Edward M
EM
Driggers
Mark A
MA
Bittinger
Hyun Gyung
HG
Jang
Masato
M
Sasaki
Shengfang
S
Jin
David P
DP
Schenkein
Shinsan M
SM
Su
Lenny
L
Dang
Valeria R
VR
Fantin
Tak W
TW
Mak
D002384:Catalysis; D005977:Glutarates / Q000097:blood; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D009154:Mutation; D009249:NADP / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
D005977:Glutarates; D007656:Ketoglutaric Acids; D011994:Recombinant Proteins; C019417:alpha-hydroxyglutarate; D009249:NADP; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human