TitleMutant IDH: a targetable driver of leukemic phenotypes linking metabolism, epigenetics and transcriptional regulation.
Publication TypeJournal Article
Year of Publication2016
AuthorsGarrett-Bakelman, Francine E., and Melnick Ari M.
JournalEpigenomics
Volume8
Issue7
Pagination945-57
Date Published2016 Jul
ISSN1750-192X
KeywordsAnimals, Epigenesis, Genetic, Gene Expression Regulation, Leukemic, Humans, Isocitrate Dehydrogenase, Mutation, Phenotype, Transcription, Genetic
Abstract

<p>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.</p>

DOI10.2217/epi-2016-0008
Alternate JournalEpigenomics
PubMed ID27431380
PubMed Central IDPMC5066133
Grant ListK08 CA169055 / CA / NCI NIH HHS / United States
R01 CA198089 / CA / NCI NIH HHS / United States