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

Losman, Julie-Aurore ; Looper, Ryan E. ; Koivunen, Peppi ; Lee, Sungwoo ; Schneider, Rebekka K. ; McMahon, Christine ; Cowley, Glenn S. ; Root, David E. ; Ebert, Benjamin L. ; Kaelin, William G.

Science (American Association for the Advancement of Science), 2013-03, Vol.339 (6127), p.1621-1625 [Periódico revisado por pares]

United States: American Association for the Advancement of Science

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Título:
(R)-2-Hydroxyglutarate Is Sufficient to Promote Leukemogenesis and Its Effects Are Reversible
Autor: Losman, Julie-Aurore ; Looper, Ryan E. ; Koivunen, Peppi ; Lee, Sungwoo ; Schneider, Rebekka K. ; McMahon, Christine ; Cowley, Glenn S. ; Root, David E. ; Ebert, Benjamin L. ; Kaelin, William G.
Assuntos: Bone marrow cells ; Brain ; Cancer ; Cell growth ; Cell Line, Tumor ; Cell membranes ; Cell Transformation, Neoplastic - genetics ; Cell Transformation, Neoplastic - metabolism ; Cellular differentiation ; Cytokines ; Enzymes ; Epics ; Genes ; Genetic mutation ; Genomics ; Glutarates - metabolism ; Hematopoiesis ; Human ; Humans ; Inhibition ; Isocitrate Dehydrogenase - genetics ; Isocitrate Dehydrogenase - metabolism ; Leukemia ; Leukemia - enzymology ; Leukemia - genetics ; Metabolites ; Models, Biological ; Mutation ; Mutations ; Procollagen-Proline Dioxygenase - antagonists & inhibitors ; Stem cells ; Strategy ; Transformations ; Transforms
É parte de: Science (American Association for the Advancement of Science), 2013-03, Vol.339 (6127), p.1621-1625
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
Descrição: 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.
Editor: United States: American Association for the Advancement of Science
Idioma: Inglês

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

Losman, Julie-Aurore ; Looper, Ryan E. ; Koivunen, Peppi ; Lee, Sungwoo ; Schneider, Rebekka K. ; McMahon, Christine ; Cowley, Glenn S. ; Root, David E. ; Ebert, Benjamin L. ; Kaelin, William G.

United States: American Association for the Advancement of Science

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