Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia

Abstract

Recent studies of the spectrum of somatic genetic alterations in acute myeloid leukemia (AML) have identified frequent somatic mutations in genes that encode proteins important in the epigenetic regulation of gene transcription. This includes proteins involved in the modification of DNA cytosine residues and enzymes which catalyze posttranslational modifications of histones. Here we describe the clinical, biological, and therapeutic relevance of mutations in epigenetic regulators in AML. In particular, we focus on the role of loss-of-function mutations in TET2, gain-of-function mutations in IDH1 and IDH2, and loss-of-function mutations in ASXL1 and mutations of unclear impact in DNMT3A in AML pathogenesis and therapy. Multiple studies have consistently identified that mutations in these genes have prognostic relevance, particularly in intermediate-risk AML patients, arguing for inclusion of mutational testing of these genetic abnormalities in routine clinical practice. Moreover, biochemical, biological, and epigenomic analyses of the effects of these mutations have informed the development of novel therapies which target pathways deregulated by these mutations. Our understanding of the effects of these mutations on hematopoiesis and potential for therapeutic targeting of specific AML subsets is also reviewed here.

Figure 1

The DNMT family of enzymes and their known effects on hematopoiesis and DNA methylation. The DNA methyltransferases DNMT1, DNMT3A, and DNMT3B catalyze methylation of CpG dinucleotides in genomic DNA. (A) The conserved domains, function, and biological effect of each DNMT member. (B) Currently, it is understood that DNMT3A and DNMT3B are essential for the establishment of DNA cytosine methylation as they catalyze the addition of methyl groups onto the C5 position of DNA cytosine residues without regard for the methylation status of DNA. In contrast, DNMT1 appears to be essential for maintenance of DNA methylation after DNA replication as DNMT1 (1) binds PCNA and (2) has preferential enzymatic activity for hemimethylated DNA over unmethylated DNA. DNMT3L, in contrast, lacks catalytic activity but appears to physically interact with DNMT3A and stimulate its enzymatic activity. PCNA, proliferating cell nuclear antigen; PHD, plant homeodomain; PWWP, proline tryptophan tryptophan proline.

Figure 2

The DNA methylation and demethylation pathway, and effect of TET2 and IDH1/2 mutations on epigenetic DNA and histone modifications. (A) The DNMT family of DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) each may place a methyl group on the C5 position of DNA cytosine residues in a reaction which requires SAM as a cofactor. (B) Members of the TET family of enzymes (TET1, TET2, TET3) may then oxidize 5-mC to 5hmC an enzymatic reaction which requires Fe(II) and α-KG as substrates. The TET family may also then iteratively oxidize 5hmC further to 5-formylcytosine followed by 5-caC. 5-caC can be directly recognized by the enzyme TDG followed by excision with the BER pathway (an enzymatic activity that is unable to excise 5hmC or 5-mC) to generate unmethylated cytosine. The AID-APOBEC DNA repair pathway can also convert 5hmC to 5-hydroxymethyluracil which activates the BER using TDG or the SMUG1 to generate unmethylated cytosines. TET-mediated enzymatic processes are dependent on α-KG. The presence of an IDH1/2 mutation results in the production of 2-HG, which is structurally very similar to α-KG and can compete with α-KG to inhibit α-KG–dependent enzymatic processes. This includes inhibition of the α-KG–dependent family of JMJC containing histone demethylases. JMJC histone demethylases are responsible for demethylation of histone ³H residues at amino acid residues 2, 4, 9, 27, and 36 and histone H4 amino acid residue 3. 5-cac, 5-carboxylcytosine; AID, activation-induced cytidine deaminase; APOBEC, apolipoprotein B mRNA editing enzyme catalytic; BER, base-excision repair; SMUG1, single-strand-selective monofunctional uracil DNA glycosylase; TDG, thymine DNA glycosylase.