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Science. 2013 Mar 29;339(6127):1621-5. doi: 10.1126/science.1231677. Epub 2013 Feb 7.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

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.

PMID:
23393090
PMCID:
PMC3836459
DOI:
10.1126/science.1231677
[Indexed for MEDLINE]
Free PMC Article
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