Besides DNA methylation, D-2-HG also increases methylation of histone by inhibiting histone demethylases such as lysine-specific demethylase (KDM).39,44 The methylation status of histone is regulated by histone methyltransferases, such as G9a, GLP, SET and EZH2, as well as by demethylases, such as KDM, LSD and JARID; similar to TET, histone demethylases such as KDM4 and KDM5 have been shown to be inhibited by high levels of D-2-HG.44 As a result, in IDH-mutated cancers, the accumulation of histone methylation markers such as H3K4me3, H3K9me3 and H3K27me3 is frequently reported. This evidence concerns the gene IDH2 and cancer.