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
either a truncated dominant negative isoform or protein
with decreased DNA binding or dimerization ability.
Approximately 85% of CEBPA mutant AMLs are biallelic
so that no wild type protein is produced, 12 and these
patients have a particularly good prognosis. 13 By contrast,
mutation of a single allele of CEBPA does not
affect prognosis. NRAS (9–14%) and KRAS (5–17%)
mutations are of uncertain prognostic significance. In
NK-AML, overexpression of the BAALC, ERG, MN1,
and EVI1 genes is associated with poor prognosis. 14,15
Poor prognosis AML includes patients with complex
karyotype (harboring at least four unrelated cytogenetic
abnormalities). 16 These patients tend to be older and
may have an antecedent myelodysplastic or myeloproliferative
disorder. Mutations involving the TP53 occur
frequently in this group (56–78%). 17 Amongst the
adverse prognosis group, multiple studies showed that
monosomal karyotype (MK), defined as autosomal
monosomy in the presence of another autosomal monosomy
or other chromosomal abnormalities, is associated
with a particularly poor prognosis, with overall survival
rates of less than 5%. 16,18,19
Single nucleotide polymorphism (SNP) arrays, which
can identify small genomic amplifications, deletions,
and areas of copy number neutral loss of heterozygosity
(LOH), also known as uniparental disomy (UPD),
showed that approximately 20% of NK-AML exhibited
partial UPD. 20 Later studies revealed that AML is characterized
by a high number of small, non-recurrent copy
number alterations. 21 SNP arrays identified TET2 as a
potential tumor suppressor in AML and other myeloid
neoplasms, as TET2 mutations are found in 24% of secondary
AML, 19% of myelodysplastic syndrome
(MDS), 12% of myeloproliferative neoplasms (MPN),
and 22% of chronic myelomonocytic leukemia
(CMML). 22 Over the past 2 years, whole-genome
sequencing discovered recurrent mutations in AML,
such as DNMT3A 23 and IDH1. 24 DNMT3A mutations
were enriched in patients with intermediate risk cytoge-
netics (33.7%) and conferred a poor prognosis. IDH1
and IDH2 mutations were found in 14% and 19% of
NK-AML, respectively and the impact of these mutations
on outcome is uncertain and may be influenced by
the presence of coincident mutations (reviewed by
Lowenberg B. in this issue). 25,26 Large-scale sequencing
also revealed mutations in ASXL1 in 6% and 53% of
patients with primary and secondary AML. 27
AML may be classified by gene expression, DNA
methylation, and chromatin modification patterns.
Gene expression profiling can predict FAB subtypes 28
and discern novel prognostic subsets of AML. 29–31 The
combination of gene expression and promoter methylation
signatures, in which the transcriptional capacity of
the genome is ascertained, can further identify AML
subtypes. 32 Figueroa et al. found 16 different patterns of
promoter methylation among AML. While some corresponded
to known cytogenetically defined subtypes,
there were five methylation-defined AML subtypes
with no other defined genetic characteristics. Several of
these groups were subsequently shown to correspond
to patients with TET2 or IDH1 or IDH2 mutations. 33
The methylation status of 15 promoters could be used
as a predictor of survival. Analysis of histone methylation
patterns in primary AML specimens may also be
useful. Profiling of H3K9 promoter methylation
revealed distinct differences between AML blasts and
normal CD34+ cells and found that the state of H3K9
methylation was a predictor of prognosis. 34 Unlike DNA
methylation profiling, however, H3K9 methylation patterns
were not associated with known cytogenetic
abnormalities and were not correlated with gene
expression.
MicroRNAs play an important role in normal
hematopoiesis and leukemogenesis. 35 Genome-wide
microRNA analysis in AML identified a correlation
between microRNA signatures, specific cytogenetic
groups, and prognosis. 36,37 In NK-AML, a microRNA
signature was identified for high-risk patients harbor-
| 28 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)
Figure 1. Stratification of
Prognostic Groups in AML.
AML patients are classified at
time of diagnosis into three
different prognostic groups
based on their cytogenetic profiles.
These groups can be further
sub-divided on the basis
of specific mutations.