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      (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible.

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          Abstract

          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)-2HG]. Elucidation of the role of IDH mutations and (R)-2HG 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)-2HG, but not (S)-2HG, despite the fact that (S)-2HG more potently inhibits enzymes, such as the 5'-methylcytosine hydroxylase TET2, that have previously been linked to the pathogenesis of IDH mutant tumors. We provide evidence that this paradox relates to the ability of (S)-2HG, but not (R)-2HG, to inhibit the EglN prolyl hydroxylases. Additionally, we show that transformation by (R)-2HG is reversible.

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          Author and article information

          Journal
          Science
          Science (New York, N.Y.)
          American Association for the Advancement of Science (AAAS)
          1095-9203
          0036-8075
          Mar 29 2013
          : 339
          : 6127
          Affiliations
          [1 ] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
          Article
          science.1231677 NIHMS512295
          10.1126/science.1231677
          3836459
          23393090
          7df6ee5a-6877-43cb-b41a-0aa21a7c5413
          History

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