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101 , 102 Gain of function mutations in IDH1 and IDH2 frequently occur in low-grade gliomas and acute myeloid leukemia, conferring a neomorphic enzyme activity that produces ( R )-2-hy-droxyglutarate ( R -2HG), which is postulated to promote, rather than inhibit, the hydroxylase activities of PHD1 and PHD2, thereby diminishing HIF signaling (reviewed by Losman and Kaelin)