R-2HG, thought to be an oncometabolite in IDH-mutant tumors, has antitumor activity in leukemia and glioma.

  • Major finding: R-2HG, thought to be an oncometabolite in IDH-mutant tumors, has antitumor activity in leukemia and glioma.

  • Mechanism: R-2HG inhibits the RNA demethylase FTO, increasing m6A and reducing MYC and CEBPA transcript stability.

  • Impact: FTO may be a potential therapeutic target in tumor cells that are sensitive to R-2HG.

Mutations in isocitrate dehydrogenase 1/2 (IDH1/2) occur frequently in patients with glioma or acute myeloid leukemia (AML) and block cell differentiation and promote tumorigenesis. Mutant IDH1/2 catalyzes the conversion of α-ketoglutarate (α-KG) to the R-enantiomer of 2-hydroxyglutarate (R-2HG), which competitively inhibits α-KG–dependent dioxygenases. Based on these findings R-2HG was considered to be an oncometabolite. However, Su, Dong, Li, and colleagues uncovered a role for R-2HG in suppressing leukemia and glioma growth. R-2HG induced cell-cycle arrest and apoptosis in the majority of a panel of leukemia cell lines as well as IDH1/2–wild-type glioblastoma cell lines. In vivo, R-2HG treatment suppressed AML progression and extended survival in leukemia xenografts. Mechanistically, R-2HG bound to the RNA demethylase FTO (an α-KG-dependent dioxygenase), competitively inhibiting its enzymatic activity and leading to an increase in levels of the internal N6-methyladenosine (m6A) RNA modification in cells sensitive to R-2HG. Consistent with this finding, FTO depletion reduced the sensitivity of leukemic cells to R-2HG. R-2HG–mediated inhibition of FTO resulted in an increase in m6A that reduced the stability of MYC and CEBPA transcripts, suppressing their expression to promote leukemogenesis. Mutant IDH1R132H had similar effects as R-2HG, inducing cell-cycle arrest and apoptosis, and decreasing proliferation in the leukemia cells that exhibited sensitivity to R-2HG in vitro and suppressing tumor growth in vivo. In AML cells, highly activated MYC signaling reduced the antileukemic effects of R-2HG, whereas cells with high levels of FTO had enhanced sensitivity to R-2HG, which may explain the seemingly conflicting roles for R-2HG in promoting and suppressing tumorigenesis. In sensitive tumor cells, R-2HG synergized with chemotherapy to suppress tumor cell growth in vitro and in vivo. Collectively, these findings reveal that R-2HG has antitumor effects in a broad range of FTO-high leukemia and glioma cells, and suggest the possibility for therapeutic targeting of FTO/MYC/CEBPA in these tumors.

Su R, Dong L, Li C, Nachtergaele S, Wunderlich M, Qing Y, et al. R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA signaling. Cell 2017;172:90–105.e23.

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