Report

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

See allHide authors and affiliations

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

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

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)-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.

View Full Text