title: (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: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Julie-Aurore
authors: JA
authors: Losman
authors: Ryan E
authors: RE
authors: Looper
authors: Peppi
authors: P
authors: Koivunen
authors: Sungwoo
authors: S
authors: Lee
authors: Rebekka K
authors: RK
authors: Schneider
authors: Christine
authors: C
authors: McMahon
authors: Glenn S
authors: GS
authors: Cowley
authors: David E
authors: DE
authors: Root
authors: Benjamin L
authors: BL
authors: Ebert
authors: William G
authors: WG
authors: Kaelin
mesh_terms: D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D005977:Glutarates / Q000378:metabolism*; D006410:Hematopoiesis; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D007938:Leukemia / Q000201:enzymology* / Q000235:genetics; D008954:Models, Biological; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D011393:Procollagen-Proline Dioxygenase
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