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

Balanced translocations
In contrast to AML, balanced translocations are seen
infrequently in MDS. The most common translocations
involve the EVI1 locus at chromosome band 3q26 and
result either in an EVI1 chimeric transcript with TEL or
AML1, or overexpression of intact EVI1. 21,22 This locus
codes for at least three isoforms. The full-length
MDS/EVI1 protein has at least partially opposing function
to the major EVI-1 isoform. 21,22 Patients whose marrow
cells overexpress EVI1 often show marked marrow
hyperplasia, dysplastic megakaryocytes, and elevated
platelet counts. 21,22 EVI1 is a transcriptional regulator that
plays an important role in the proliferation of hematopoietic
stem cells, and overexpression in AML may be an
independent negative prognosticator. 21,22 Enforced overexpression
of EVI1 in mouse marrow cells results in death
due to pancytopenia in 10 to 13 months. 23 EVI1 interacts
with histone deacetylases (HDACs) and histone methyltransferases,
as well as DNA methyltransferases
(DNMTs), and increased expression of EVI1 in AML
blasts is associated with gene repression through hypermethylation
of specific promoters. 24 Two subclusters
with increased EVI1 expression have been reported in
AML, one of which is associated with rearrangement of
band 3q26 and with monosomy 7. 24 Less frequently,
translocations involving RUNX1, NUP98, TEL, MEL1,
and IER3 are seen in MDS. 25
Copy number alterations and copy neutral loss
of heterozygosity LOH
Recent application of genome-wide technologies,
such as array comparative genomic hybridization
(aCGH) and single nucleotide polymorphism arrays
(SNP-A), have revealed smaller deletions and amplifications
of chromosomes not detectable by standard karyotyping.
26-28 Early data suggest that incorporation of
these aberrations into clinical algorithms allows better
risk stratification than the IPSS score alone, and novel
recurrent alterations may provide further insight into
London, United Kingdom, June 9-12, 2011
Figure 2. Relative proportions
of the different cytogenetic
aberrations seen
in MDS. 20 This figure only
represents the subset of
patients (approximately
half) that show karyotypic
anomalies.
the pathogenesis of MDS karyotyping. 26-28 In addition to
copy number alterations, SNP-A can also detect copy
neutral LOH, also referred to as uniparental disomy,
which result from loss of one chromosome or chromosomal
region with concomitant duplication of the
retained allele. Copy neutral LOH is common in
myeloid malignancies. 29 First identified as a mechanism
of JAK2V617F homozygosity in myeloproliferative neoplasms,
additional homozygous mutations due to copy
neutral LOH, for example, TET2, EZH2, CBL, have been
identified in MDS. 29
Molecular alterations associated with large
chromosomal aberrations
Identifying the causal genes involved in the pathogenesis
of MDS when whole or large tracts of chromosomes
are deleted is difficult. However, the task has
been assisted both by application of SNP-A, as well as
the painstaking characterization – over many years by
several investigators – of the proximal and distal breakpoints
from groups of patients to define commonly
deleted regions (CDRs).
Del(5q)
Perhaps the greatest understanding of MDS has come
from the study of the most common genetic anomaly
observed in the disease, del(5q). 20 5q- syndrome, or
MDS with isolated del(5q), is characterized by macrocytic
anemia, variable neutropenia, normal or elevated
platelet counts with dysplastic hypolobated megakaryocytes,
and low propensity to develop AML. 30 Two distinct
CDRs have been defined on chromosome arm 5q:
one at 5q31 and the other at 5q32-33. 31,32 The distal 1.5
Mb CDR is associated with the classic 5q- syndrome,
that is, macrocytic anemia, variable neutropenia, and
elevated platelet counts associated with dysplastic
hypolobulated megakaryocytes. 31 This region encompass-
Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 219 |