141

Epigenetics and Myelodysplastic Syndrome

epigenetics
methyl
DNA (DNA methylation), histone
micro RNA (miRNA)

epigenetics
myelodysplastic syndrome

DNA
DNA
(phenotype)

epigenetics1 epigenetics
(reversible)
(genetics)
(irreversible) epigenetics

myelodysplastic syndrome
Epigenetics
Epigenetics

DNA
3 transcription
factor
1-3
eukaryotic cell
nucleosome
DNA histone histone complex
histone complex histone 8
4 histone H2A, H2B, H3 H4
histone H2A H2B H3
H4 transcription

1 Chromatin structure comprising nucleosomes

(Modified from reference 5)
nucleosome DNA histone
complex 2 1 nucleosome DNA
147 (base pairs)
2 3
1. Euchromatin
interphase active
transcription
2. Heterochromatin (condensed)
cell cycle transcription factor

epigenetics 3
DNA methylation, histone modification miRNA
regulation DNA methylation
histone modification
(gene silencing)
2,3
1. DNA methylation2,3,4

(embryonic stem cell)

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142

(multipotent)
(euchromatin)
transcription

heterochromatin histone
transcription (repression)

methyl (methylation) DNA

CpG nucleotide cytosine
(C) guanine (G) CpG nucleotide
CpG island
transcription promoter DNA
methylation cytosine
promoter CpG island CpG
island methylation transcription
promoter
X (X inactivation)
genetic imprinting

DNA methylation
cytosine 5-methylcytosine (5mC)
methyl C-5 cytosine residue
DNA methyltransferase (DNMT) CpG island
methylation methylatedDNA binding proteins MECP2
transcription (transcriptional
co-repressors) histone modification
histone deacetylases (HDAC)
transcription factor
(gene
silencing) 2 DNA methylation

methyl histone
histone H3 lysine9 (H3K9)6
DNA methylation promoter

growth factor,
cytokine
DNA methylation
methylation
DNMTs
methylation CpG methylation
methylation CpG
island transcription tumor
suppressor gene
allele allele
hypermethylation
DNA methylation

2. Histone modification2,3,4
Histone H3 H4
tail amino acid
methylation, acetylation, phosphorylation,
ubiquination sumoylation

histone modification histone
histone (histone code)
transcription
histone
histone acetyltransferases (HATs), histone
deacetylase (HDACs), histone methyltransferases (HMTs)
histone demethylases (HDMs) nucleosome
transcription factor

2 DNA methylation (Modified from reference 4)

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Epigenetics and Myelodysplastic Syndrome

143

3 Various mechanisms of histone modification (Modified from reference 4)

nucleosome
transcription factor transcription

histone modification

transcription factor
histone
HAT HDAC complex promoter
histone modification 3
3
1. Histone acetylation acetyl
lysine N terminus histone
acetyl DNA
DNA histone RNA polymerase
transcription factor promoter
histone acetyltransferased (HATs)
acetylation histone H3
H4
2. Histone deacetylation DNA
histone transcription
factor promoter repression
histone deacetylases (HDACs)

3. Histone methylation methyl

histone histone methyltransferases
(HMT) histone methylation

histone transcription
methylation
histone H3K4 transcription
H3K9 H3K27 7
DNA methylation
histone modification
transcription transcription
DNA methylation
histone acetylation
transcription
DNA methylation histone
acetylation DNA
methylation histone modification
2 DNA
methylation histone
modification methyl-binding protein
histone methylation
DNA methylation 2
methylcytosine
methyl CpG binding protein 2 (MECP2 MBD2)
histone deacetylase
methylation
histone modification


translocation PML-RARA

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144

acute promyelocytic leukemia

(AML-M3) HDAC
8

histone
acetyltransferase CBP
9, MLL gene H3K4 methylase
10 EZH2
H3K27 tri-methylase
11 methylation promoter
12
3. MicroRNA (miRNA) regulation4
miRNAs RNA

transcription miRNA
transcription
RNA-induced silencing complex (RISC) mRNA
(complementary)
translation mRNA (translational
repression)

mRNA miRNAs
antago-miRNAs miRNA

miRNA 700
10 100 miRNA

miRNA
oncogene tumor
suppressor gene MDS
del(5q) miR-145, miR-146a
miR-150 13
miRNA MDS
miRNA
Epigenetic MDS4,14
MDS
(cytogenetic)
50 MDS
(conventional
cytogenetics)
MDS
MDS



4 MDS
(bone marrow hypercellularity)
complete blood count

(apoptosis)

4 The model demonstrating the pathogenesis of myelodysplastic syndrome (Modified from reference 4)
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Epigenetics and Myelodysplastic Syndrome

MDS
(chromosome loss)

epigenetics
Knudson
two-hits
MDS epigenetics
MDS DNA methylation
transcription DNA
methylation promoter
cell cycle (CKDN2A), (DAPK1,
RIL), (CDH1,
CDH13) MDS hypermethylation
4
epigenetic 2
MDS4,15,16
1. hypermethylation gene promoter
MDS AML
(gene silencing)
hypermethylation promoter
cell adhesion molecule, cell cycle tumor
suppressor gene
MDS CDKN2B (P15)
methylation 30-80 MDS
deletion 5q 7q
17,18

145

DNA methylation
hypermethylation MDS
DNA methylation MDS
epigenetic

(AML) DNA methylation

(reversible)
azacytidine, decitabine
DNMT inhibitor methylation 19,20
DNA methylation
MDS DNMT3A, TET2 IDH1/2
DNA methylation
methylation 5 cytosine CpG
dinucleotides DNA methyltransferases
(DNMTs) DNMT3A DNMT3B
5-methylcytosine (5mC)
Ten Eleven Translocation (TET) TET1, TET2
TET3 5mC 5-hydroxymethylcytosine
(5hmC) demethylation
cytosine 5hmC
TET alpha-ketoglutarate (KG)
KG isocitrate
isocitrate dehydrogenase1 2 (IDH1/2)
isocitrate KG
DNMT3A, TET2 IDH1/IDH2
cytosine methylation gene

5 Epigenetic changes in MDS both inDNA methylation and histone modification (modified from reference 21)
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146

transcription 5mC 5hmC21 5

1.1 DNMT3A
AML 8% MDS
arginine histidine 882 (R882H)
DNMT3A
MDS

1.2 TET2 missense,

frame shift nonsense myeloid
MDS 11-26, MDS/MPN (myelodysplastic syndrome/
myeloproliferative neoplasm) 37-44
sAML (secondary acute myeloid leukemia) 11-24
TET2
5hmC
TET2
1.3 IDH1/IDH2
MDS 4-11 sAML 8-10
IDH1

2. post-translational modification histone

histone modification
DNA methylation
MDS valproic acid HDAC inhibitor22,23
histone 24
2.1 EZH2 enhancer
of zeste homolog 2 polycomb
methylation histone H3 K27 (lysine
27) transcription
EZH2
2-6 MDS
2.2 ASXL1 additional
sex comb-like 1
transcription ASXL1
MDS 11-15
Myelodysplastic syndrome/
myeloproliferative neoplasm (MDS/MPN)24
CMML (chronic
myelomonocytic leukemia) MDS/MPN
NRAS KRAS 1
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3

CMML
TET2 CBL
CMML ASXL1, RUNX1
EZH2
epigenetics
myelodysplastic
syndrome

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