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Supplementary Table S6 from (R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers

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posted on 2023-06-02, 08:21 authored by Kathryn Gunn, Matti Myllykoski, John Z. Cao, Manna Ahmed, Bofu Huang, Betty Rouaisnel, Bill H. Diplas, Michael M. Levitt, Ryan Looper, John G. Doench, Keith L. Ligon, Harley I. Kornblum, Samuel K. McBrayer, Hai Yan, Cihangir Duy, Lucy A. Godley, Peppi Koivunen, Julie-Aurore Losman

Supplementary Table S6 shows the mutational profiles of the primary AML patient samples subjected to H3K4me3 ChIP-seq.

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National Cancer Institute (NCI)

United States Department of Health and Human Services

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Sidney Kimmel Foundation (SKF)

William Guy Forbeck Research Foundation (WGFRF)

Wong Family

Dana-Farber Cancer Institute (DFCI)

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ARTICLE ABSTRACT

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 (R)-2-hydroxyglutarate [(R)-2HG], an oncometabolite that is hypothesized to promote cellular transformation by dysregulating 2OG-dependent enzymes. The only (R)-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 (R)-2HG has other functionally relevant targets in IDH-mutant cancers. Here, we show that (R)-2HG inhibits KDM5 histone lysine demethylases and that this inhibition contributes to cellular transformation in IDH-mutant AML and IDH-mutant glioma. These studies provide the first evidence of a functional link between dysregulation of histone lysine methylation and transformation in IDH-mutant cancers. 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 (R)-2HG accumulation in IDH-mutant cells. Here, we provide evidence that KDM5 inhibition by (R)-2HG contributes to mutant IDH–mediated transformation in AML and glioma.This article is highlighted in the In This Issue feature, p. 1275

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