Several mutations associated with acute myelogenous leukemia (AML) lead to the same metabolic change, report Gross and colleagues.
Mutations in the enzyme isocitrate dehydrogenase 1 (IDH1) occur in about 80% of secondary brain cancer tumors, and in nearly a tenth of AML tumors. Normally, IDH1 catalyzes a critical step in glucose metabolism in the cytoplasm—the conversion of isocitrate into α-ketoglutarate. However, when the amino acid arginine at position 132 of IDH1 mutates, the enzyme acquires new powers. It reduces α-ketoglutarate into R(-)-2-hydroxyglutarate (2-HG), an “onco-metabolite” recently linked to the development of brain cancer and here, to AML.
The authors find that AML patients with IDH1 mutations at position 132 harbor high serum levels of 2-HG. However, the mutations from AML patients often differed from those of brain cancer patients by an amino acid; instead of primarily switching to histidine, arginine had frequently changed to cysteine. And the cysteine variant showed a higher affinity for α-ketoglutarate, which led to more 2-HG. The team uncovered an additional mutation in IDH2, IDH1's counterpart that acts in the peroxisome. Likewise, this mutant IDH2 enzyme converted α-ketoglutarate into 2-HG.
Although the effect of 2-HG on tumor growth is unknown, the authors speculate that it may promote tumor progression by elevating reactive oxidative species or by altering cell metabolism by inhibiting key enzymes. In any case, because these ID1H mutations appear to be unique to cancer, they provide promising targets for drugs and biomarkers of the disease.