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; IDH; epigenomics; histone tail methylation; hydroxymethylcytosine; leukemogenesis; mutation; targeted therapy; transcriptional regulation.

Figure 1.. Overview of the IDH–TET2–WT1 leukemogenic axis.

Mitochondrial and cytosolic IDH enzymes as well as a subset of normal enzymatic steps from the TCA cycle are represented (blue box). In IDH mutant cells, IDH1 and IDH2 neomorphic enzymes (IDH1m and IDH2m) produce the oncometabolite 2-HG at high levels. 2-HG can inhibit the function of dioxygenase enzymes, including epigenetic modifiers (TET2, JMJC). TET2 and JMJC inhibition results in elevated levels of 5mC and histone lysine methylation respectively. These changes result in transcriptional dysregulation, which facilitates the acquisition of proliferative advantage and/or cell differentiation blockade. Malignant transformation can occur in IDHm cells in the presence of cooperative mutations. Mutations in WT1 (WT1m) that disrupt TET2 recruitment to WT1-target genes result in an alternative mechanism for transcriptional dysregulation and cell differentiation blockade. α-KG: α-ketoglutarate; 2-HG: (R)-enantiomer of 2-hydroxyglutarate; HKme: Methylated histones; hmC: Hydroxymethylcytosine; HMume: Unmethylated histones; IDHm: Mutant IDH enzymes; mC: Methyl-cytosine; TCA: Tricarboxylic acid.

Figure 2.. IDH1 and IDH2 mutations in malignant disorders.

cBioPortal [22,23] frequency plots of amino acid substitutions resulting from mutations in IDH1 (A) and IDH2 (B) in malignant disorders (all cancer studies included). Green = missense mutations; red = inframe mutations (inframe deletion or insertion); black = truncating mutations (nonsense, nonstop, frameshift deletion, frameshift insertion, splice site); purple = other mutations (all other mutation types).