H e m a t o lo g y E d u c a t io n - European Hematology Association

16 th Congress of the European Hematology Association
Patients with an isolated trisomy 8 are placed in the
intermediate prognostic risk group. 20 A proportion of
trisomy 8 patients respond well to immune suppression,
although the +8 clone often persists and may
actually expand. 13 It has been suggested that the +8
clone is resistant to killing by cytotoxic T cells, and
that immune suppression then allows the clone to
expand at the expense of normal hematopoietic elements.
13
Epigenetic changes in myelodysplastic
syndromes
Epigenetics is the study of persistent changes in phenotype
through mechanisms that do not involve a
change in the DNA sequence. 58 Epigenetic changes
allow expression patterns to be preserved when cells
divide. One of the major ways that cell phenotype is
maintained is through the remodeling of chromatin.
The mechanisms of chromatin remodeling are complex
and dynamic, requiring interactions between transcription
factors, noncoding RNAs, and DNA, and histone
modifying enzymes. 59-61 However, as a framework,
chromatin remodeling can be thought to be accomplished
through two main mechanisms: 1. Post-translational
modifications of the tails of histone proteins,
which changes the physical structure of chromatin.
These modifications can act to either compact the
DNA around the histones, such that chromatin is in a
closed confirmation and transcription is repressed (e.g.,
H3K27me3, H3K9me3, H3/H4 deacetylation), or to
open chromatin to permit transcriptional activation
(e.g., H3K4me3, H3K36me3, H3/H4 acetylation); 2.
DNA methylation that converts cytosine to 5-methylcytosine
usually at CpG sites through DNA methyltransferases
(DNMTs). 59-61 Highly methylated regions,
particularly at CpG islands residing at promoters, tend
to be less transcriptionally active. 58 DNMT1 has preference
for hemimethylated DNA and thus is important
for maintaining methylation patterns following cell
division. 62 DNMT3s, in contrast, have de novo methyltransferase
activity, and appear to have preferred target
CpG sites. 62
In cancers, there is commonly global hypomethylation
of DNA with concomitant hypermethylation at
specific sites, usually CpG islands of specific promoters.
63 The hypermethylated genes include the promoters
of several bona fide or putative tumor suppressor
genes, including CDKN2B, FHIT, and HIC. 64 In MDS
and secondary AML, aberrant DNA methylation
involving specific chromosomal regions and thousands
of genes has been described. 24,65,66 Genes in the WNT
and MAPK signaling pathways appear to be prominently
involved, and the aberrant methylation pattern is
reversed following combination therapy with 5-azacytidine
and an HDAC inhibitor. 65 Over recent years, it
has become apparent that several recurrent mutations
found in cancer target genes are involved in epigenetic
regulation. In acute leukemias, the histone acetyltransferase,
CBP, has been found to be mutated, and the
H3K4 methylase, MLL, is often rearranged. However, it
is only recently that mutations affecting epigenetic regulation
have been identified in MDS (Figure 4).
Point mutations in genes associated
with epigenetic modifying functions
Specific mutation frequencies in MDS vary from
study to study and appear to depend on the subtype of
MDS or MDS/MPN interrogated. Similarly, given that
many of these point mutations are only just beginning
to be identified in MDS, the prognostic value of specific
mutations can be contentious. In addition, expression
levels for some of these factors have also been found to
be altered in MDS.
In 2009, several groups independently identified frequent
mutations, copy neutral LOH, or microdeletions
at chromosome band 4q24, the locus of the TET2 gene,
in MDS, MDS/MPN, AML, secondary AML and
CMML. 67-72 It is likely that TET2 mutations occur in a
hematopoietic stem cell or very early progenitor as the
mutations are found in both CD34 + stem/progenitor
cells and CD3 + T cells. 73 TET2 is an enzyme that converts
5-methylcytosine to 5-hydroxymethylcytosine in
DNA, and the mutations associated with myeloid
malignancies impair catalytic activity. 74,75 TET2 knockdown
in mouse hematopoietic progenitor cells favored
monocyte/macrophage differentiation in cultures. 74
While one group has reported global hypomethylation
of DNA in the context of TET2 mutations (which is paradoxical
given the putative role of wild-type TET2 in
promoting cytosine demethylation), another group has
found a specific hypermethylation signature with TET2
mutation associated with a tendency for gene repression
at these sites. 74,75 Further studies are needed to clarify
this issue, and to determine the prognostic implications
of loss of TET2 function.
The IDH1 mutation was first identified following
whole genome sequencing of the leukemic cells of a
patient with normal karyotype AML. 76 Subsequently
mutations in IDH2, the mitochondrial homologue, were
also found. 75,77 Most commonly mutations occur at
IDH1-R132 in MDS, 78,79 whereas in AML, IDH2-R140 or
IDH2-R172 mutations are also found. 80 Studies suggest
that IDH1 mutations portend a poorer prognosis in MDS
and AML, and may play a pathogenic role in disease evolution.
77,79-81 Although the IDH genes encode isocitrate
dehydrogenases, the IDH1-R132 and the IDH2-R172
active site mutants display a gain of function that results
in conversion of α-ketoglutarate to 2-hydroxyglutarate,
which accumulates in leukemic cells with the IDH2-
R172K mutation. 82 IDH1 and IDH2 mutations are mutually
exclusive and are always heterozygous as the wild
type allele is important for cell proliferation. 82 IDH1/2
mutations are also mutually exclusive with mutations in
TET2, and interestingly, the 2-hydroxyglutarate produced
by the mutant IDH proteins interferes with the
conversion of 5-methylcytosine to 5-hydroxymethylcytosine
by TET2. 75 Consistent with this data, these
authors found that mutations in IDH1/IDH2 share an
overlapping hypermethylation phenotype with mutant
TET2 cells, and expression of mutant IDH1/2 or TET2
depletion impaired hematopoietic differentiation and
increased stem/progenitor cell marker expression, suggesting
a common mechanism of leukemogenesis. 75
As described above, EZH2 (chromosome band 7q36)
is the catalytic subunit of the polycomb repressive complex
2 (PRC2), which functions as a histone H3 lysine 27
| 222 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)