(R)-2-Hydroxyglutarate Is Sufficient for Leukemic Transformation

Recurrent mutations in IDH1 and IDH2, which encode the isocitrate dehydrogenase enzymes required to convert isocitrate to α-ketoglutarate, have been identified in leukemias and glioblastomas. These mutations result in neomorphic enzymatic activity that converts isocitrate to (R)-2-hydroxyglutarate, which accumulates in cells and leads to deregulation of α-ketoglutarate–dependent enzymes such as histone demethylases, methylcytosine dioxygenases, and prolyl hydroxylases. Although (R)-2-hydroxyglutarate production is presumed to be the mechanism by which IDH mutations drive tumorigenesis, it has not been formally demonstrated that (R)-2-hydroxyglutarate is sufficient for transformation. To directly address this question, Losman and colleagues used a human erythroleukemia cell line that is unique in its cytokine dependence and capacity for erythropoietin (EPO)-induced differentiation. Cells treated with a cell membrane-permeable version of (R)-2-hydroxyglutarate became cytokine independent and lost the ability to differentiate in response to EPO, qualities that are indicative of leukemic transformation, whereas the (S)-enantiomer of 2-hydroxyglutarate did not confer cytokine independence or block differentiation. A short hairpin RNA screen of α-ketoglutarate–dependent enzymes showed that knockdown of Tet methylcytosine dioxygenase 2 (TET2) phenocopied the effects of mutant IDH1 expression or (R)-2-hydroxyglutarate treatment, suggesting that TET2 inhibition by (R)-2-hydroxyglutarate contributes to transformation of IDH-mutant cells. This result seemed paradoxical because (R)-2-hydroxyglutarate is a weaker inhibitor of TET2 than (S)-2-hydroxyglutarate, which did not promote leukemic transformation. However, unlike (R)-2-hydroxyglutarate, which activates EGLN prolyl hydroxylases, (S)-2-hydroxyglutarate antagonizes EGLN proteins, which were required for cytokine-independent growth and blockade of EPO-induced differentiation. Of note, cellular transformation by (R)-2-hydroxyglutarate was reversible, as cells regained their differentiation capacity and cytokine dependence upon its removal. These findings implicate (R)-2-hydroxyglutarate as an oncometabolite that can promote oncogenic transformation, and suggest that inhibitors of (R)-2-hydroxyglutarate production or EGLN activity might be effective in IDH-mutant cancers.

Losman JA, Looper R, Koivunen P, Lee S, Schneider RK, McMahon C, et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 2013 Feb 7 [Epub ahead of print].