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.

Keywords::

• AML
• DNA methylation
• epigenomics
• histone tail methylation
• hydroxymethylcytosine
• IDH
• leukemogenesis
• mutation
• targeted therapy
• transcriptional regulation

Financial & competing interests disclosure

The authors wish to thank the following sources of financial support: NCI R01CA198089 to AM Melnick, NCI K08CA169055 and funding from the American Society of Hematology (ASHAMFDP-20121) under the ASH-AMFDP partnership with The Robert Wood Johnson Foundation to FEG Bakelman. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

The authors wish to thank the following sources of financial support: NCI R01CA198089 to AM Melnick, NCI K08CA169055 and funding from the American Society of Hematology (ASHAMFDP-20121) under the ASH-AMFDP partnership with The Robert Wood Johnson Foundation to FEG Bakelman. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.