The epigenetic landscape of acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Certain cytogenetic and molecular genetic mutations are recognized to have an impact on prognosis, leading to their inclusion in some prognostic stratification systems. Recently, the advent of high-throughput whole genome or exome sequencing has led to the identification of several novel recurrent mutations in AML, a number of which have been found to involve genes concerned with epigenetic regulation. These genes include in particular DNMT3A, TET2, and IDH1/2, involved with regulation of DNA methylation, and EZH2 and ASXL-1, which are implicated in regulation of histones. However, the precise mechanisms linking these genes to AML pathogenesis have yet to be fully elucidated as has their respective prognostic relevance. As massively parallel DNA sequencing becomes increasingly accessible for patients, there is a need for clarification of the clinical implications of these mutations. This review examines the literature surrounding the biology of these epigenetic modifying genes with regard to leukemogenesis and their clinical and prognostic relevance in AML when mutated.

Figure 1

This Venn diagram highlights some of the key mutations found in AML and suggests classes to which these mutations could be ascribed.

Figure 2

Figure showing methylation of cytosine residues at CpG sites. The addition of a methyl group to convert the DNA base cytosine to 5-methylcytosine is catalyzed by DNA methyltransferase (DNMT). The methyl group is transferred from S-adenosylmethionine (SAM) to the 5-carbon position of cytosine.

Figure 3

Methylation of CpG islands reduces gene transcription and is purported to play a role in malignancy through reduced expression of tumor suppressors and genes concerned with differentiation. Global hypomethylation is also frequently observed in malignant cells, and while it is likely that there is genetic instability and promotion of protooncogene expression, the exact role of global methylation patterns in the development of cancer is uncertain.

Figure 4

Histone tail modifications include methylation, acetylation, phosphorylation, ADP-ribosylation, and ubiquitination. Of these modifications, methylation and acetylation have the most influence on chromatin structure. Histone acetylases (HATs) catalyze acetylation of the histone tails, and histone deacetylases (HDACs) reverse acetylation. Histone methylation can involve mono-, di-, or trimethylation of arginine and lysine residues of one of the highly conserved histone units.

Figure 5

Transcriptionally active euchromatin has high levels of histone acetylation and enriched trimethylation of H3K4, H3K36, or H3K79 residues. Conversely, transcriptionally repressed heterochromatin is enriched in trimethylated H3K9, K3K27, and H4K20 and has reduced histone acetylation, mediated by HDAC activity. Heterochromatinization of euchromatin loci is induced by the binding of heterochromatin protein 1 (HP1) to methylated H3K9 and mediated by corepressor proteins such as retinoblastoma protein (pRb) and KAP1. Demethylation of specific histone residues is mediated by a number of histone demethylase enzymes, including LSD1 and Jumonji C-domain proteins (the latter mentioned above in relation to IDH mutations).