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

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.

• Authors: Julie-Aurore Losman, Ryan E Looper, Peppi Koivunen, Sungwoo Lee, Rebekka K Schneider, Christine McMahon, Glenn S Cowley, David E Root, Benjamin L Ebert, William G Kaelin Jr
• Journal: Science (New York, N.Y.) (Science) Vol. 339 Issue 6127 Pg. 1621-5 (Mar 29 2013) ISSN: 1095-9203 [Electronic] United States
• PMID: 23393090 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Glutarates
• alpha-hydroxyglutarate
• Isocitrate Dehydrogenase
• IDH1 protein, human
• Procollagen-Proline Dioxygenase

Topics

• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics, metabolism)
• Glutarates (metabolism)
• Hematopoiesis
• Humans
• Isocitrate Dehydrogenase (genetics, metabolism)
• Leukemia (enzymology, genetics)
• Models, Biological
• Procollagen-Proline Dioxygenase (antagonists & inhibitors)