The Impact of Epigenetic Modifications in Myeloid Malignancies

Abstract

Myeloid malignancy is a broad term encapsulating myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Initial studies into genomic profiles of these diseases have shown 2000 somatic mutations prevalent across the spectrum of myeloid blood disorders. Epigenetic mutations are emerging as critical components of disease progression, with mutations in genes controlling chromatin regulation and methylation/acetylation status. Genes such as DNA methyltransferase 3A (DNMT3A), ten eleven translocation methylcytosine dioxygenase 2 (TET2), additional sex combs-like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2) and isocitrate dehydrogenase 1/2 (IDH1/2) show functional impact in disease pathogenesis. In this review we discuss how current knowledge relating to disease progression, mutational profile and therapeutic potential is progressing and increasing understanding of myeloid malignancies.

Keywords: AML; ASXL1; DNMT3A; EZH2; Epigenetics; IDH1; IDH2; MDS; MPN; TET2.

Figure 1

Analysis of co-occurrence and co-expression of epigenetic genes and other cellular regulatory processes. Interactions shown between genes considered to possess epigenetic modification processes and other cellular processes like transcriptional regulation and signalling and kinase pathways highlighting the intricate pathway association needing accounted for in the progression of knowledge around mutational profiles within myeloid malignancies.

Figure 2

Analysis of DNMT3A molecular structure, active tetramer structure, mechanism of action and drug target action. (A) Domain structure of mammalian DNMT3A enzyme consisting of 912 amino acid residues. Green highlighting PWWP domain which is required for directing DNA methylation. Blue highlighting ADD (ATRX-DNMT3A-DNMT3L) motif responsible for mediating protein–protein interaction to transcription factors. Red highlights the C-terminal MTase domain contains highly conserved regions of C5-DNA methyltransferases. Additionally, highlighted is the structural position of the most common mutation occurring within DNMT3A (R882). (B) Active tetramer formed from two DNMT3A and two DNMT3L molecules resulting in an increased affinity for DNA causing more efficient methylation. (C) Mechanism of action for both wild-type (WT) DNMT3A and the truncated mutant DNMT3A. WT DNMT3A causing methylation which can reduce expression of gene expression compared to mutant DNMT3A which can often result in increased expression of genes depending on the context of the cellular function occurring.

Figure 3

Analysis of TET2 molecular structure, mechanism of action and drug target action. (A) Domain structure of mammalian TET2 enzyme consisting of 2002 amino acid residues. Green highlighting a cystine rich domain comprised of two sub-domains which modulate chromatin targeting by TET proteins. Blue highlighting the iron binding domain which interacts with double stranded β-helix domain (yellow) and α-ketoglutarate binding domain (red) to form a core catalytic region. DSBD also contains a low complexity insert whose function remains unclear. (B) Mechanism of action for both wild-type TET2 and the mutant TET2. WT TET2 causing conversion of 5-mC (purple circle) into 5-hmC (green), 5-fC (yellow) or 5-caC (blue). Mutated TET2 lowers expression resulting in overexpression of 5-hmC causing control over genes being switched on or off.

Figure 4

Analysis of IDH molecular structure, mechanism of action and drug target action. (A) Domain structure of mammalian IDH1 enzyme consisting of 414 amino acid residues and IDH2 consisting of 452 amino acids. Blue highlighting a large domain. Green highlighting the small domain. Red highlighting clasp domain which links other subunits together. IDH2 also contains a mitochondrial targeting sequence. Additionally, highlighted is the structural position of the most common mutation occurring within IDH1 (R132) and IDH2 (R140/172). (B) Mechanism of action for both wild-type IDH and the mutant IDH. WT IDH causing production of α-KG enabling TET2 to function in demethylation of DNA causing potential increased gene expression. Mutated IDH inhibits TET2 function due to production of 2-HG expression often resulting decreased gene expression.

Figure 5

Analysis of EZH2 molecular structure, PRC2 structure, mechanism of action for wild-type and mutant and drug target action. (A) Domain structure of mammalian EZH2 enzyme consisting of 751 amino acid residues. Green highlighting WDB (WD-40 binding domain). Yellow highlighting domain ‘1’ which binds PHF1 and domain ‘2’ binding region for SUZ12. Blue highlighting SANT domain allowing interaction of chromatin remodelling proteins with histones. Red highlights cytosine rich domain. Purple highlighting catalytic SET domain. (B) Model of mammalian PRC2 complex with core subunits. (C) Mechanism of action for wild-type EZH2 showing trimethylation of H3K27 resulting in gene transcription silencing. (D) Mechanism of action for PRC2 containing mutant EZH2 showing reduced methylation of H3K27 resulting in increased gene transcription.

Figure 6

Analysis of ASXL1 molecular structure, ASXL1/PRC2 structure, PR-DUB structure, and mechanism of action for wild-type and mutant ASXL1. (A) Domain structure of mammalian ASXL1 enzyme consisting of 1541 amino acid residues. Green highlighting HARE-HTH (HB1, ASXL1 restriction endonuclease helix-turn-helix). Yellow highlighting DEUBAD (deubiquitinase adaptor). Blue highlighting c terminal PHD domain. (B) Model of mammalian PRC2 complex with core subunits and association with ASXL1. (C) Model of PR-DUB complex with BAP1 and ASXL1. (D) Mechanism of action for both wild-type and mutant ASXL1 in relation to function with PRC2. Wild-type ASXL1 contributes to ubiquitination of H2AK119 enabling stabilization of PRC2 leading to trimethylation of H3K27 resulting in transcriptional silencing. Mutant ASXL1 causes deubiquitylation of H2SK119 preventing the stabilization of PRC2 resulting in reduced methylation of H3K27 resulting in increased gene transcription.