(R)-2-Hydroxyglutarate is Sufficient to Promote Leukemogenesis and its Effects are Reversible

By J. Losman, R. Looper, P. Koivunen, Sungwoo Lee, R. Schneider, C. McMahon, G. Cowley, D. Root, Benjamin L. Ebert, W. Kaelin. Science, 2013

705 citations recorded by the source corpus.

Focusing on the Right Metabolite A variety of human cancers, including acute leukemias and brain tumors, have mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1, IDH2), which cause overproduction of a metabolite called 2-hydroxyglutarate (2HG). Losman et al. (p. 1621, published online 7 February) show that the R- but not the S-enantiomer of 2HG can transform cells and that R-2HG mediates transformation at least in part through effects on protein modifying EglN prolyl hydroxylases. Importantly, the transforming activity of R-2HG was reversible, suggesting that therapeutic strategies focusing on inhibition of R-2HG production or inhibition of EglN prolyl hydroxylases merit further investigation. A metabolite specific to certain cancers, and of therapeutic interest, exists in two forms, only one of which is oncogenic. 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.

Subfields: Cancer Research, Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d50891d3a667ae0ebaa9fd5742875f24c6b32dad

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Citations in the corpus

R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling (2017, background): “…leukemia, we exposed 27 human leukemia cell lines (Table S1), none of which carries common IDH1/2 mutations (Table S2), to a series of concentrations of R-2HG; similar or even higher concentrations of R-2HGhave been used in previous studies (Fu et al., 2015; Losman et al., 2013; Lu et al., 2012).”
RNA N6-methyladenosine modification in cancers: current status and perspectives (2018, background): “R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, which could be found in 10–20% of AML patients, ~80% of grade II-III gliomas and secondary GBM, and at a lower rate in other cancers, was reported as an oncometabolite.61–68 For instance, m”
Targeting Metabolism for Cancer Therapy (2017, background): “These epigenetic changes caused by D-2HG contribute to cancer phenotypes (Losman et al., 2013; Rohle et al., 2013; Saha et al., 2014; Wang et al., 2013), and have been proposed to promote oncogenesis by preventing normal cellular differentiation (Losman and Kaelin, 2013).”
Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “D2HG regulates the HIF-1 signaling axis HIF-1 protein levels are precisely controlled by PHDs, also known as Eglnine homologs (EGLNs), which are α-KG-dependent dioxygenases that function as cellular oxygen sensors.”
Mitochondrial metabolism and cancer (2017, background): “That said, however, it should be noted that (1) RCD regulation at mitochondria involves a robust metabolic (rather than purely structural) component; (2) several metabolic aspects of the mitochondrial biology also influence therapeutic responses [101, 169] and (3) metabolic enzymes residing within m”
HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. (2013, neutral): “The effects of D-2-hydroxygluta-rate as an oncometabolite may be due in part to its inhibition of the 5 ′ -methylcytosine hydroxylase TET2 (96).”