IDH1R132-mutant Cells Have Decreased Ataxia Telangiectasia Mutated (ATM) and Impaired DNA Damage Response, Which Occur Independently From Effects of Mutant Isocitrate Dehydrogenase 1 (IDH) on TET2. IDH1 normally serves in the tricarboxylic acid (TCA) cycle to convert isocitrate to α-ketoglutarate (αKG). Mutations in IDH1 and IDH2 confer a change-of-function of these enzymes causing them to convert αKG to the oncometabolite 2-hydroxyglutarate (2HG). 2HG competitively inhibits αKG-dependent enzymes, which includes the methylcytosine dioxygenase enzyme TET2, the Jumonji C-domain–containing family of histone lysine demethylases (JHDM), and more than 80 additional enzymes. In their article, Dr. Satoshi Inoue and colleagues identify that IDH1R132H-mutant cells have reduced expression of ATM, at least partly due to increased histone H3 lysine 9 (H3K9) trimethylation at the ATM locus. This results in reduced long-term hematopoietic stem cells and impaired DNA damage response in IDH1-mutant cells, which are features not seen in TET2-mutant cells. This stands in contrast to DNA 5-methylcytosine (mC) and 5-hydroxymethylcytosine (hmC), which are similarly altered in TET2- and IDH1-mutant cells.