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Leukaemia Section
Review
11q23 rearrangements in de novo childhood acute
myeloid leukemia
Eva A Coenen, Jochen Harbott, Christian Michel Zwaan, Susana C Raimondi, Mary M van den
Heuvel-Eibrink
Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The
Netherlands (EAC, CMZ, MMv), Acute Myeloid Leukemia-Berlin-Frankfurt-Munster Study Group,
Department of Pediatric Hematology and Oncology, Justus-Liebig-University, Giessen, Germany (JH),
Department of Pathology (Room 4023A), St. Jude Children's Research Hospital, 332 North Lauderdale
Street, Memphis, Tennessee 38105-2794, USA (SCR)
Published in Atlas Database: March 2012
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/11q23ChildAMLID1615.html
DOI: 10.4267/2042/47495
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Etiology
Identity
There is strong molecular evidence that 11q23
abnormalities in pediatric leukemia occur in utero. The
MLL gene has an important role in normal
hematopoietic
growth
and
differentiation.
Abnormalities in this region can occur very early in
hematopoietic stem cell development.
In utero exposure to natural or synthetic substances that
inhibit topoisomerase II (e.g., genistein, catechins,
flavonoids) may result in acute leukemia.
It has been suggested that rearrangement of the MLL
gene leads to the inhibition of apoptosis and
leukemogenesis.
Acute leukemias of myeloid (AML) and lymphoid
(ALL) lineage have 11q23/MLL rearrangements but
show a different predilection for translocation partners,
which are thought to be responsible in part for
development of the phenotype of each type of
leukemia.
The brief latency of infant acute leukemias involving
11q23/MLL rearrangements suggests that the MLL
fusions need some additional cooperating mutations to
cause leukemia.
Recent array comparative genomic hybridization
(aCGH) and high-throughput genomic studies have
confirmed these findings.
Note
Clinical aspects of 11q23 abnormalities in de novo
childhood acute myeloid leukemia (AML) are
described.
Clinics and pathology
Disease
Childhood acute myeloid leukemia and 11q23/MLL
rearrangement
Phenotype/cell stem origin
Leukemic cells with 11q23 abnormalities typically
disrupt the MLL gene; they frequently have a
myelomonoblastic or monoblastic morphology (FAB
M4,
M5)
with
accompanying
myeloblastic
immunophenotype of moderate CD45, low SSC,
CD13+, CD33+, CD34+, CD117+, HL-DR+ and
monoblastic immunophenotype of bright positive
CD45, low SSC, CD11b+, CD11c+, CD13+, CD14+,
CD33+, CD64+, CD4+, CD56+, HLA-DR+.
Additional cytogenetic lesions are present in
approximately 50% of patients with an 11q23/MLL
rearrangement, with trisomy 8 being the most frequent
(18%). (See Table 1).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(8)
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11q23 rearrangements in de novo childhood acute myeloid leukemia
Coenen EA, et al.
Table 1. Occurrence of different MLL rearrangements according to the French American British (FAB) morphology type in an
international retrospective study of 756 pediatric patients with 11q23/MLL rearranged AML. * Patients with a clearly indicated subband were classified heir respective categories; other patients for whom data on subband or translocation partner were insufficient were
classified as noted. Data obtained from an international retrospective study of 756 pediatric patients with 11q23/MLL rearranged AML
(Balgobind et al., Blood 2009).
Table 2. Occurrence of different MLL rearrangements by age at diagnosis in an international retrospective study of 756
pediatric patients with 11q23/MLL rearranged AML. * Percentage within the indicated age group. ¶ Patients with a clearly indicated
sub-band were classified heir respective categories; other patients for whom data on subband or translocation partner were insufficient
were classified as noted. Data obtained from an international retrospective study of 756 pediatric patients with 11q23/MLL rearranged
AML (Balgobind et al., Blood 2009).
Table 3. Occurrence of different MLL rearrangements by clinical parameters in an international retrospective study of 756
pediatric patients with 11q23/MLL rearranged AML. * Percentage within the 11q23 abnormality group. ¶ Patients with a clearly
indicated sub-band were classified heir respective categories; other patients for whom data on subband or translocation partner were
insufficient were classified as noted. Data obtained from an international retrospective study of 756 pediatric patients with 11q23/MLL
rearranged AML (Balgobind et al., Blood 2009).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(8)
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11q23 rearrangements in de novo childhood acute myeloid leukemia
Coenen EA, et al.
retrospective study consisting of 756 pediatric patients
with 11q23 abnormalities and AML in which the
overall 5-year event free survival (EFS) rate was 44%.
(See Table 2).
Epidemiology
Depending on the method of detection, the overall
incidence of 11q23 abnormalities among children with
AML ranges from 15% to 25%.
In children younger than 2 years, the peak incidence of
11q23/MLL gene rearrangements is 50%-60%. By
contrast, the incidence of 11q23 abnormalities in adults
with AML is approximately 5%, and these
abnormalities are rarely seen in patients older than 60
years. Also, patients with second leukemias, especially
those administered prior epipodophyllotoxin II
treatment, have a high incidence of 11q23 aberrations,
but these are not dealt with in detail here. An estimated
5%-10% of MLL rearrangements in AML are subtle or
cryptic and need to be detected by fluorescence in situ
hybridization (FISH) using the MLL probe,
preferentially in a sequential G-banded and FISH
metaphase to identify the partner chromosome.
Most of the following information was obtained from a
large international collaborative
Clinics
Children with 11q23/MLL rearranged AML often
present with high white blood cell counts (WBC),
central nervous system (CNS) involvement and
organomegaly. (See Table 3).
Treatment
In most pediatric AML protocols, patients with
11q23/MLL rearrangements are treated according to
intermediate-risk stratification.
Stem cell transplantation is not generally advised in
first complete remission.
A recent study, however, showed significant benefit of
matched sibling donor stem cell transplantation for
11q23-rearranged pediatric AML patients in first
complete remission in the AML-BFM 98 protocol.
Table 4. Outcomes of patients by univariate analysis of different MLL rearrangements and as per clinical and laboratory
parameters, from an international retrospective study of 756 pediatric patients with 11q23/MLL rearranged AML. Abbreviations:
pEFS, probability of event free survival; pCIR, probability of cumulative incidence of relapse; pOS, probability of overall survival; SE,
standard error; WBC, white blood cell count. * P-values of indicated abnormality as compared to 11q23/MLL-rearranged pediatric AML
patients with other additional cytogenetic abnormalities. ¶ Patients with a clearly indicated sub-band were classified heir respective
categories; other patients for whom data on subband or translocation partner were insufficient were classified as noted. Data obtained
from an international retrospective study of 756 pediatric patients with 11q23/MLL rearranged AML (Balgobind et al., Blood 2009).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(8)
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11q23 rearrangements in de novo childhood acute myeloid leukemia
Coenen EA, et al.
Table 5. Hazard ratios from multivariate analysis of different MLL rearrangements and according to additional cytogenetic
aberrations, from an international retrospective study of 756 pediatric patients with 11q23/MLL rearranged AML. Abbreviations:
EFS, event free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; P, P-value; ACAs, additional cytogenetic
aberrations. * P<0.05; † P<0.01. ¶ Patients with a clearly indicated sub-band were classified heir respective categories; other patients for
whom data on subband or translocation partner were insufficient were classified as noted. Data obtained from an international
retrospective study of 756 pediatric patients with 11q23/MLL rearranged AML (Balgobind et al., Blood 2009).
32%, respectively, whereas patients with the most
frequent specific additional aberration trisomy 8 had a
5-year EFS of 53%. (See Table 4 and Table 5).
Prognosis
The prognostic significance of 11q23 abnormalities in
children with AML is unclear, but it appears to depend
on the partner gene involved and additional
chromosomal aberrations. Most of the work presented
here is from an international collaborative retrospective
study consisting of 756 pediatric patients with 11q23
abnormalities and AML in which the overall 5-year
EFS rate was 44%. The outcome of the subgroups
varied greatly; for example, patients with a
t(1;11)(q21;q23) had an excellent outcome (5-year
EFS, 92%) whereas those with a t(6;11)(q27;q23) had
the worst outcome (5-year EFS, 11%). Subgroups
t(10;11)(p12;q23),
t(4;11)(q21;q23),
and
t(10;11)(p11.2;q23) had a 5-year EFS of 31%, 29%,
and 17%, respectively. The prognosis of the most
commonly occurring partner t(9;11) is controversial
and will be described later. In this retrospective study,
patients younger than 10 years had a more favorable
prognosis than those 10 years or older (EFS of 46% and
34%, respectively) (P=0.006).
The presence of specific additional cytogenetic
aberrations was significantly correlated with outcome.
Patients with trisomy 19 and structural additional
cytogenetic aberrations had a 5-year EFS of 17% and
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(8)
Cytogenetics
Cytogenetics morphological
t(9;11)(p22;q23)
- The t(9;11)(p22;q23) is the most frequent 11q23/MLL
abnormality in pediatric AML, occurring in
approximately 50% of patients.
- The fusion gene resulting from this translocation
involves MLL and AF9 (MLLT3).
- Additional cytogenetic aberrations have been detected
by conventional karyotyping in approximately 47% of
patients with t(9;11)(p22;q23). The most frequently
recurring additional aberration is trisomy 8 (~24%).
- There is no consensus on the outcome of patients with
t(9;11). A 5-year EFS of 50% and a 5-year OS of 63%
were reported in an international retrospective study.
However, the Nordic countries (NOPHO) and St. Jude
Children's Research Hospital (St. Jude), Memphis, TN,
USA, have reported that patients with t(9;11)(p22;q23)
had better prognosis than patients with other
translocation partners, with a 7-year EFS of 86% in the
577
11q23 rearrangements in de novo childhood acute myeloid leukemia
AML. However, this incidence is underestimated as the
DNA exchanged in this translocation is very subtle and
may go undetected or be misclassified as a
del(11)(q23).
- The fusion gene resulting from this translocation
involves MLL and AF6 (MLLT4). RT-PCR is also a
very useful method to identify the MLL-AF6 fusion
transcript.
- In approximately 46% of t(6;11)(q27;q23) cases,
additional cytogenetic aberrations have been detected
by conventional karyotyping. The most frequent
recurring additional aberrations are trisomy 8 and
trisomy 21 (~17% each) and additional structural
aberrations (~26%).
- A 5-year EFS of 11% and a 5-year OS of 22% have
been reported in a large international retrospective
study; t(6;11)(q27;q23) thus represents the subgroup
with the worst outcome in pediatric 11q23/MLL
rearranged AML, but the reason for the very poor
survival rate is unknown.
t(11;19)(q23;p13)
- Translocations of chromosome 11q23 with
chromosome 19p13 occur in approximately 12% of
pediatric patients with 11q23/MLL rearranged AML.
Two common translocation partners are present on
19p13: ELL on 19p13.1 and ENL (MLLT1) on
19p13.3. In approximately 33% of pediatric AML
cases, resolution of the karyotype can be insufficient to
define the sub-band with certainty, and for this
publication these patients are grouped as
t(11;19)(q23;p13).
- A 5-year EFS for patients with a t(11;19)(q23;p13),
t(11;19)(q23;p13.1), and t(11;19)(q23;p13.3) of 49%,
46% and 46% respectively, and a 5-year OS of 49%,
61% and 47%, respectively, have been reported in a
large international retrospective study.
t(1;11)(q21;q23)
- The t(1;11)(q21;q23) occurs in approximately 3% of
all pediatric patients with 11q23/MLL rearranged
AML.
- The fusion gene resulting from this translocation
involves MLL and AF1q (MLLT11).
- In approximately 25% of t(1;11)(q21;q23) cases,
additional cytogenetic aberrations have been detected
by conventional karyotyping, the most frequent being
trisomy 6 (13%).
- A 5-year EFS of 92% and a 5-year OS of 100% have
been reported in a large international retrospective
study; t(1;11)(q21;q23) thus represents the subgroup
with the best outcome in pediatric 11q23/MLL
rearranged AML.
NOPHO-AML93 trial and a 5-year EFS of 65% in the
4 consecutive St. Jude trials (1980 to 1997).
- In some protocols, treatment of t(9;11)(p22;q23) is
done according to low-risk stratification, but this
approach is controversial.
t(10;11)(p12;q23)
- The t(10;11)(p12;q23) is the second most frequent
11q23/MLL abnormality in pediatric AML, accounting
for approximately 13% of all cases of 11q23/MLL
rearranged pediatric AML.
However, this percentage is underestimated, because in
many instances the generation of the fusion gene is
cryptic or complex (see below). It is difficult to
accurately establish the breakpoints of 10p in many
translocations involving 10p and 11q23.
- The fusion gene resulting from this translocation
involves MLL and AF10 (MLLT10).
- To generate an MLL-AF10 fusion, the translocation
of chromosome 10 and chromosome 11 has to include
at least one inversion. Most t(10;11)(p12;q23) cases are
identified by conventional karyotyping, but structural
aberrations can be very complex. These aberrations
include insertions of 11q material onto the 10p arm and
vice versa, some of which are also cryptic. In some
instances, FISH using the subtelomeric probes for 10p
and 11q can clarify the nature of the abnormality. RTPCR is also a very useful method to detect the MLLAF10 fusion transcript.
- In approximately 50% of the t(10;11)(p12;q23) cases,
additional cytogenetic aberrations have been detected
by conventional karyotyping. The most frequently
recurring additional aberration is trisomy 8 (~7%);
diverse structural additional aberrations have been
detected (36%) and can affect other chromosomes.
- A 5-year EFS of 31% and a 5-year OS of 45% were
reported in a large international retrospective study.
t(10;11)(p11.2;q23)
- The t(10;11)(p11.2;q23) is a rare 11q23/MLL
abnormality mainly found in young children with
AML. However, in the large retrospective study, 3 of
12 (25%) patients were older than 2 years.
- The fusion gene resulting from this translocation
involves MLL and ABI1.
- In approximately 58% of t(10;11)(p11.2;q23) cases,
additional cytogenetic aberrations have been detected
by conventional karyotyping, all cases displaying at
least one additional structural aberration.
- A 5-year EFS of 17% and a 5-year OS of 27% were
reported in a large international retrospective study.
t(6;11)(q27;q23)
- The t(6;11)(q27;q23) occurs in approximately 5% of
all pediatric patients with 11q23/MLL rearranged
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(8)
Coenen EA, et al.
578
11q23 rearrangements in de novo childhood acute myeloid leukemia
Coenen EA, et al.
Figure 1. Survival curves of different MLL rearrangements, from an international retrospective study of 756 pediatric patients with
11q23/MLL rearranged AML (Balgobind et al., Blood 2009).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(8)
579
11q23 rearrangements in de novo childhood acute myeloid leukemia
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Cytogenetics molecular
Approximately 5% to 10% of cases of AML and an
MLL gene rearrangement are not detectable by
conventional
cytogenetic
methods.
Currently,
commercially available dual-color MLL break-apart
probes are available that allow FISH evaluation of
rearrangement in the interphase nuclei and
identification of the partner/derivative chromosome on
metaphase chromosomes. In rare instances, segments of
the MLL probe may be deleted when generating the
rearrangement; thus FISH may also detect a concurrent
deletion of 3'MLL and rarely of 5'MLL.
As mentioned throughout, molecular cytogenetic
methods have shown that the frequency of MLL gene
rearrangements exceeds that of 11q23 translocations
detected by conventional cytogenetic method alone. In
AML cases in which aberrations affect the 11q23 band,
a complementary FISH study should be done to
determine whether a rearrangement of MLL is present,
as in rare cases an 11q23 translocation may involve
genes other than MLL. In AML patients with normal
karyotypes or without an identified type II aberration
[such as t(8;21), t(15;17) or inv(16)], FISH might
identify a cryptic MLL rearrangement. Because the
translocation partners for 11q23 are numerous and
markedly heterogeneous, additional molecular methods
may be needed to further assess the partner genes for
MLL. RT-PCR is suitable to evaluate the most
frequently observed MLL fusion transcripts, and, if
positive, can also be useful for following the status of
the patient's minimal residual disease. In other cases,
long-distance inverse PCR on genomic DNA can aid
the finding of uncommon or novel translocation
partners.
MLL-partial tandem duplication is a separate entity that
can only be identified by PCR or other techniques, and
is not discussed here.
Genetic lesions also occur frequently in 11q23/MLL
rearranged pediatric AML. In approximately 43% of
cases, a mutation in one of the RAS-pathway coding
genes, FLT3 or KIT, has been identified.
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This article should be referenced as such:
Coenen EA, Harbott J, Zwaan CM, Raimondi SC, van den
Heuvel-Eibrink MM. 11q23 rearrangements in de novo
childhood acute myeloid leukemia. Atlas Genet Cytogenet
Oncol Haematol. 2012; 16(8):574-581.
Coenen EA, Raimondi SC, Harbott J, Zimmermann M, Alonzo
TA, Auvrignon A, Beverloo HB, Chang M, Creutzig U, Dworzak
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(8)
Coenen EA, et al.
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