title: Mutant IDH: a targetable driver of leukemic phenotypes linking metabolism, epigenetics and transcriptional regulation.
abstract: Aberrant epigenomic programming is a hallmark of acute myeloid leukemia. This is partially due to somatic mutations that perturb cytosine methylation, histone post-translational modifications and transcription factors. Remarkably, mutations in the IDH1 and IDH2 genes perturb the epigenome through all three of these mechanisms. Mutant IDH enzymes produce high levels of the oncometabolite (R)-2-hydroxyglutarate that competitively inhibits dioxygenase enzymes that modify methylcytosine to hydroxymethylcytosine and histone tail methylation. The development of IDH mutant specific inhibitors may now enable the therapeutic reprogramming of both layers of the epigenome spontaneously to revert the malignant phenotype of these leukemias and improve clinical outcome for acute myeloid leukemia patients with IDH mutations.
authors.affiliation: Division of Hematology/Medical Oncology, Department of Medicine, Weill Cornell Medicine, 413 East 69th Street, BRB 14th floor, New York, NY, USA.
authors.forename: Francine E
authors.initials: FE
authors.lastname: Garrett-Bakelman
authors.affiliation: Division of Hematology/Medical Oncology, Department of Medicine, Weill Cornell Medicine, 413 East 69th Street, BRB 14th floor, New York, NY, USA.
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
mesh_terms: D000818:Animals; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D014158:Transcription, Genetic
chemical_list: C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: AML; DNA methylation; IDH; epigenomics; histone tail methylation; hydroxymethylcytosine; leukemogenesis; mutation; targeted therapy; transcriptional regulation