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

(H3K27) methyltransferase, and is associated with transcriptional
repression. 54 EZH2 also physically interacts
with all three DNA methyltransferases (DNMTs). 53
Together these findings would implicate loss of EZH2 in
reducing H3K27 trimethylation (and possibly DNA
methylation), and thereby potentially activating a subset
of pathogenic genes. Of interest, conditional inactivation
of Ezh2 in the mouse hematopoietic system did
not have demonstrable effects on myeloid function,
although B cell development was defective, thus additional
studies will be needed to address its role in
myeloid malignancies. 83
Similar to IDH1, a DNA methyltransferase mutation,
DNMT3A, was identified following whole genome
sequencing of the leukemic cells of a patient with normal
karyotype AML. 84 In this study, 62 of 281 patients
(22%) had DNMT3A mutations that were predicted to
affect translation, most commonly affecting amino acid
R882. These mutations were highly enriched in AML
patients with an intermediate-risk cytogenetic profile
and were associated with poor outcome. More recently
12/150 patients (8%) with MDS were found to have
DNMT3A mutations. 85 As DNMT3A mutations likely
result in loss of function, one would predict that there
would be reduced DNA methylation, which would possibly
correspond to global hypomethylation. However,
EVI1 has been shown to interact with DNMT3A, and
increased expression of EVI1 favors promoter hypermethylation.
24 Interestingly, expression of miR-29b which
directly targets DNMT3A (and 3B) mRNA is reduced in
a subset of AML and enforced miR-129b expression
results in global hypomethylation. 86
ASXL1 truncation mutations, which are likely loss of
function mutations, have recently been reported to be
frequent in myeloid malignancy, including MDS. 56,57
ASXL1 can act in repressor or activator complexes
depending on the cellular context and has been found to
associated in a histone H2A deubiquitinase complex. 77
ASXL1 is also a member of a repressive complex containing
histone H1.2. 87 ASXL1 may function as an activator
or repressor of retinoic acid receptor signaling, and
also regulates HOX genes. 77 ASXL1 is expressed in most
hematopoietic cell types, but mice targeted for the gene
only display mild defects in myelopoiesis, do not appear
to have hematopoietic stem cell defects, and do not
develop myeloid malignancy. 87 Of note, one report suggests
that the most commonly reported variant in
ASXL1, a duplication of G in exon 12 (codon G646W)
may not be a somatic alteration, and thus the frequency
of ASXL1 mutations may be significantly lower than
originally thought. 88 Further studies are clearly needed.
Several other less well-studied mutations in MDS target
epigenetic modifiers, such as UTX. 56 As well, differential
expression of epigenetic modifiers, such as
increased JMJD3 and H3K27 demethylase, have also
been described. 89 The coming years will paint a better
picture of how defects in chromatin remodeling contribute
to MDS pathogenesis.
Other point mutations observed in
myelodysplastic syndromes
While it is not the intent by any means to suggest that
London, United Kingdom, June 9-12, 2011
all mutations somehow lead to epigenetic modifications,
it is important to note that several previously
identified mutations that have been shown to function
in other pathways are also known to play a role in chromatin
remodeling.
TP53 is a tumor suppressor gene located at chromosome
band 17p13 that functions to protect the genome
against stress-induced damage by regulating various
pathways, including apoptosis, cell cycle, senescence,
DNA repair, and cell metabolism. 90 TP53 mutations
occur frequently in MDS patients with a complex karyotype,
particularly in the presence of del(17p), -
5/del(5q), and -7/del(7q), but are usually exclusive of
many of the point mutations listed above. 91-93 P53 interacts
with histone acetyltransferases and methyltransferases,
as well as DNMTs. 94,95 In del(5q) MDS, p53 is
activated by the stress induced by impaired ribosomal
biogenesis, but although depletion of p53 abrogates the
hematopoietic progenitor defect in a mouse model,
mutations in TP53 are associated with transformation to
AML in del(5q) MDS. 35,96
RUNX1 (AML1) mutations are commonly found in
MDS and minimally differentiated AML, although
translocations involving the RUNX1 locus at chromosome
band 21q22 are only seen in AML. 97-99 RUNX1
mutations are frequently seen in RAEB, as well as therapy-
and radiation-related MDS/AML. 97,98 Heterozygous
germline mutations of RUNX1 result in familial platelet
disorder characterized by platelet abnormalities and a
predisposition to MDS/AML. However, families with
normal platelet counts and function have been
described. 100 The molecular pathogenesis of RUNX1related
myeloid malignancies may be distinct depending
on the mutation. 98 N-terminal in-frame mutations are
thought to cooperate with -7/del(7q), as well as with
activating RAS mutations. 97,98 Runx1 is required for initiating
definitive embryonic hematopoiesis from the
hemogenic endothelium. 101 Although Runx1 can act as a
repressor, it mainly functions as a transcriptional activator
in association with CBFβ or other partners, by
recruiting histone acetyltransferases and methyltransferases.
97,98,102 Evi1 has been shown to interact with
Runx1 and inhibit its DNA binding capability. 103
As with several of the other mutations, NRAS and less
frequently KRAS mutations are more frequently found
in higher-risk MDS and MDS/MPN overlap syndromes,
and result in activation of the MAP kinase and NF-κB
pathways. 104,105 There is also evidence to suggest that
DNA-methylation associated repression of tumor suppressors
and apoptotic genes are partly regulated by Ras
signaling. 106 Ras-activating mutations may not be as frequent
as previously thought. Similarly to RAS, JAK2
(chromosome 9p24) and CBL (chromosome 11q23)
mutations are usually associated with MDS/MPD overlap
syndromes. 77 JAK2-V617F mutations are usually
found in the provisional category of RARS with thrombocytosis
(RARS-T). 77 JAK2 is a non-receptor tyrosine
kinase that has transforming activity in part through the
activation of STAT5. However, recently JAK2 was also
found to localize to the nucleus where it can phosphorylate
histone H3 on Tyr 41 (H3Y41) in a STAT5-independent
manner. 107 Phosphorylation of H3Y41 results in
transcriptional derepression at specific genes through
the release of the transcriptional repressor heterochro-
Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 223 |