Mutant IDH: a targetable driver of leukemic phenotypes linking metabolism, epigenetics and transcriptional regulation.

Epigenomics
Francine E Garrett-Bakelman, Ari Melnick

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.

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Citations

Mar 28, 2017·Biomolecules·A G M MostofaKalkunte S Srivenugopal
Mar 16, 2018·Future Oncology·Guillermo Montalban-Bravo, Courtney D DiNardo
Apr 21, 2020·Expert Review of Hematology·Xavier ThomasMaël Heiblig
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May 12, 2018·Nature Communications·Daniel TemkoTrevor A Graham
Sep 22, 2020·Minerva medica·Maria Paola MartelliClaudio Cerchione
Apr 10, 2021·Blood Reviews·Marcos de LimaGert Ossenkoppele

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Methods Mentioned

BETA
PCR
methylation profiling
transfection
transgenic

Clinical Trials Mentioned

NCT01915498
NCT02074839
NCT01385150

Software Mentioned

ERRBS

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