(R)-2-Hydroxyglutarate Is Sufficient to Promote Leukemogenesis and Its Effects Are Reversible

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Science  07 Feb 2013:
DOI: 10.1126/science.1231677

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Mutations in IDH1 and IDH2, the genes coding for isocitrate dehydrogenases 1 and 2, are common in several human cancers, including leukemias, and result in overproduction of the (R)-enantiomer of 2-hydroxyglutarate [(R)-2-HG]. Elucidation of the role of IDH mutations and (R)-2-HG in leukemogenesis has been hampered by a lack of appropriate cell-based models. Here we show that a canonical IDH1 mutant, IDH1 R132H, promotes cytokine independence and blocks differentiation in hematopoietic cells. These effects can be recapitulated by (R)-2-HG, but not (S)-2-HG, despite the fact that (S)-2-HG more potently inhibits enzymes previously linked to the pathogenesis of IDH mutant tumors, such as the 5′-methylcytosine hydroxylase TET2. We provide evidence that this paradox relates to the ability of (S)-2-HG, but not (R)-2-HG, to inhibit the EglN prolyl hydroxylases and, importantly, show that transformation by (R)-2-HG is reversible.

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