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- W4367609529 abstract "<div>Abstract<p>Oncogenic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 occur in a wide range of cancers, including acute myeloid leukemia (AML) and glioma. Mutant IDH enzymes convert 2-oxoglutarate (2OG) to <i>(R)</i>-2-hydroxyglutarate [<i>(R)</i>-2HG], an oncometabolite that is hypothesized to promote cellular transformation by dysregulating 2OG-dependent enzymes. The only <i>(R)</i>-2HG target that has been convincingly shown to contribute to transformation by mutant IDH is the myeloid tumor suppressor TET2. However, there is ample evidence to suggest that <i>(R)</i>-2HG has other functionally relevant targets in <i>IDH</i>-mutant cancers. Here, we show that <i>(R)</i>-2HG inhibits KDM5 histone lysine demethylases and that this inhibition contributes to cellular transformation in <i>IDH</i>-mutant AML and <i>IDH</i>-mutant glioma. These studies provide the first evidence of a functional link between dysregulation of histone lysine methylation and transformation in <i>IDH</i>-mutant cancers.</p>Significance:<p>Mutant IDH is known to induce histone hypermethylation. However, it is not known if this hypermethylation is functionally significant or is a bystander effect of <i>(R)</i>-2HG accumulation in <i>IDH</i>-mutant cells. Here, we provide evidence that KDM5 inhibition by <i>(R)</i>-2HG contributes to mutant IDH–mediated transformation in AML and glioma.</p><p><i><a href=https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-13-6-ITI target=_blank>This article is highlighted in the In This Issue feature, p. 1275</a></i></p></div>" @default.
- W4367609529 created "2023-05-02" @default.
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- W4367609529 date "2023-06-02" @default.
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- W4367609529 title "Data from <i>(R)</i>-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in <i>IDH</i>-Mutant Cancers" @default.
- W4367609529 doi "https://doi.org/10.1158/2159-8290.c.6624819" @default.
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