Download High incidence of Hox11L2 expression in children with T-ALL

Leukemia (2002) 16, 2417–2422
 2002 Nature Publishing Group All rights reserved 0887-6924/02 $25.00
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High incidence of Hox11L2 expression in children with T-ALL
L Mauvieux1,2, V Leymarie1, C Helias1, N Perrusson2, A Falkenrodt1, B Lioure3, P Lutz4 and M Lessard1 ,2
1
Laboratoire d’Hématologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; 2Laboratoire d’Hématologie Cellulaire, Université
Louis Pasteur, CNRS EA 3431, Strasbourg, France; 3Département d’Onco-hématologie, Hôpital Hautepierre, Strasbourg, France; and 4Service
d’Onco-hématologie Pédiatrique, Hôpital Hautepierre, Strasbourg, France
The orphan homeobox gene HOX11L2 was previously found to
be transcriptionally activated as a result of the t(5;14)(q35;q32)
translocation in three T-ALL cases. We now tested by RT-PCR
Hox11L2 expression in 23 consecutive cases of T-ALL (15 children aged 0.8–14 years, eight adults aged 17–55 years) and as
control 13 B-ALL patients from a single institution. Hox11L2
expression was undetectable in all patients with B-ALL, nor in
adults with T-ALL. Nine children (60% of the cases), all boys,
expressed Hox11L2. Blast cells from most of the latter patients
carried surface CD1a, CD10 and not CD34 antigens, in contrast
to the other children. FISH , M-FISH and IPM-FISH analysis
failed to detect a t(5;14)(q35;q32) in one of them, which suggests a possible distinct genetic mechanism in Hox11L2
expression induction. Hence, Hox11L2 expression seems to be
the most frequent abnormality in childhood T-ALL to date, comparable to the t(12;21) in child B-ALL.
Leukemia (2002) 16, 2417–2422. doi:10.1038/sj.leu.2402709
Keywords: T-ALL; childhood; Hox11L2; t(5;14)(q35;q32); FISH
Introduction
Recurrent chromosomal abnormalities are detectable in about
50% of T-ALL using conventional cytogenetics,1 and can be
divided into two main categories: deletions and translocations. Detectable deletions, as for example 9p deletions,2
lead to inactivation of the tumor suppressing genes p15 and
p16, or invisible deletions on the short arm chromosome 1
activate the transcriptional regulatory factor Tal1.3 Translocations carry regulatory sequences of TCR genes close to
target genes, leading to their inappropriate expression during
T cell development. This is notably the case for
t(11;14)(p13;q11), which juxtaposes LMO2 and TCR␣/␦ or
TCR␤,4,5 t(10;14)(q24;q11), in which the homeoprotein gene
Hox11 is placed under the control of the TCR␣/␦ gene,6,7 and
t(1;14)(p32;q11) which joins TAL1 with TCR segments on
der(14).8 Conventional cytogenetic techniques fail to identify
all abnormalities, due to the frequent poor quality of chromosome banding in T cell proliferations, which display a ‘normal
karyotype’. Innovating techniques (FISH, multi-FISH and spectral karyotype) have been of considerable interest in analysis
of those difficult cases.
Recently, we observed a new recurrent cryptic translocation
in about 22% of T-ALL in the first series described,9,10 the
t(5;14)(q35;q32). This translocation, cryptic using the conventional cytogenetics (R or G banding), is only detectable by
FISH and/or multi-FISH analysis, correlated with the
expression of the developmental gene HOX11L2, which is
localized closed to breakpoints on chromosome 5. This transcriptional regulator, closely related to Hox11, is critical for
the development of the ventral medullary respiratory center,
Correspondence: M Lessard, Laboratoire d’Hématologie, Hôpital
Hautepierre, Avenue Molière, 67085 Strasbourg Cedex, France; Fax:
(33) (0)3 88 12 75 55
The first two authors participated equally in this work
Received 25 March 2002; accepted 24 June 2002
and its deficiency in KO mice results in a syndrome resembling congenital central hypoventilation.11 As Hox11L2
expression in T-ALL is thought be the specific consequence of
t(5;14)(q35;q32) translocation, we analyzed Hox11L2
expression by RT-PCR in a panel of consecutive T-ALL with
available frozen material, in order to evaluate its incidence
(independently of cytogenetic data), and the possible correlations with immunophenotype data.
Materials and methods
Patients
Cryopreserved material was obtained after informed consent
in 23 consecutive (from 1994 to 2001) T-ALL patients
followed-up in Hôpital Hautepierre, Strasbourg, France and
retrospectively studied. Eight were adults (17–55 years old, six
male, two female), and 15 were children: 11 male, four
female, aged from 10 months to 14 years. Diagnosis of T-ALL
was made according to the morphological and cytochemical
criteria of the French–American–British classification and by
immunophenotyping. All children were included in EORTC
therapeutic trials. Three patients (Nos 2, 3 and 7) have already
been described.9 The control group consisted of 13 B-ALL
(three adults and 10 children).
Cytogenetics
Cytogenetic studies were performed on bone marrow or on
blood blast cells if bone marrow was not available. Cells were
cultured using three different modes: a 17 h overnight incubation with Colcemid at low concentration (10 ␮g/10ml of
RPMI 1640 medium), and 24 h and 48 h cultures with FRDU
synchronization in order to improve the quality of the banding. RHG banding techniques were applied in every case.12
Each case was analyzed using a dual-color chromosome
paint, following the instructions of the manufacturer
(DNACoat; Appligene Oncor, Illkirch, France). Chromosome
5 probe was labeled with Spectrum Green (SG) and chromosome 14 probe was labeled with Spectrum Orange (SO). In
order to confirm and precisely define the breakpoints, unique
sequence probes were also hybridized: YAC 885A6
(5q35)(CEPH library), BAC 45L16 and BAC 546B8 (5q35)
(kindly provided by R Berger, U434 INSERM-CEPH, Paris,
France) and IgH (14q32)(LSI IGHc/IGHv dual-color break
apart probe, Vysis, Voisins le Bretonneux, France). YAC
885A6, BAC 45L16 and BAC 546B8 were amplified by AluPCR, labeled with digoxigenin and detected with a rhodamine
anti-digoxigenin antibody. IgH probe (14q32) was used
according to the manufacturer’s instructions. The first three
cases were identified using IPM-FISH and published elsewhere (for details see Refs 9 and 13). In all cases, at least 20
mitosis were studied. Patient No. 8 was further studied using
Hox11L2 expression in children T-ALL
L Mauvieux et al
2418
␮g of RNA was subsequently reverse transcribed using
SuperscriptII reverse transcriptase. The resulting cDNA was
PCR amplified (30 cycles, denaturation at 94ºC during 30 s,
annealing at 60ºC during 30 s, extension at 72ºC during 30
s), using Hox11L2 primers derived from an already published
report10 (No. 005: 5′-GCGCATCGGCCACCCCTACCAGA-3′,
No. 006 5′-CCGCTCCGCCTCCCGCTCCTC-3′). Specific
amplification of Hox11L2 was confirmed by direct sequencing
of PCR products with internal primers: No. 011: 5′AACCGGACGCCGCCCAAGCG-3′ and No. 012: 5′GCCTCCCGCTCCTCCGCCGTCT-3′, using dRhodamine Dye
Terminator Mix on ABI 3100 sequencing apparatus. The
expression of Hox11L2 was assayed in the control group of
13 B-ALL by RT-PCR, from previously extracted total RNA.
cDNA quality was assessed for T-ALL and B-ALL samples
using ␤-actin primers (UA 5′-ATCATGTTTGAGACCTTCAA3′, AL 5′-CATCTCTTGCTCGAAGTCCA-3′).
interphase nuclei FISH in 250 nuclei using YAC 885A6 probe
and in 300 nuclei using BAC45L16 and BAC 546B8.
For image acquisition of dual-color and multi-FISH, an epifluorescence microscope Leica DMR-XA (Leica Microsystemes, Rueil-Malmaison, France) fitted with Leica special filters was used, according to Speicher et al14 and Eils et al.15
Immunophenotyping
At diagnosis, mononuclear cell fractions containing more than
90% leukemic cells were isolated from blood and/or bone
marrow samples by centrifugation on Ficoll–Hypaque. Surface
and intracytoplasmic antigens were detected by flow cytometry (FACScan or FACScalibur, Becton Dickinson, Le Pont de
Claix, France) using labeled specific monoclonal antibodies
(Table 1) and negative isotypic controls. Immunophenotypic
features of the patients’ blast cells were classified using the
European Group for the Immunological Characterization of
Leukemias (EGIL) recommendations.16 Briefly, EGIL T-I (proT ALL) was defined by the presence of CD7, T-II (pre-T ALL)
by that of CD2 and/or CD5 and/or CD8, T-III (cortical T-ALL)
by CD1a, and T-IV (mature T-ALL) by surface CD3 and lack of
CD1a. Bi-phenotypic ALL was defined according to the EGIL
scoring system based on the expression of myeloid and
lymphoid antigens.16
Statistical analysis
Statistical analysis was performed using Fischer’s exact test on
Instat software package (GraphPad Software, San Diego, CA,
USA). Survival curves and Mann–Whitney non-parametric test
were performed on Prism software (GraphPad Software).
Molecular studies
Results
HOX11L2 expression was studied in the 23 T-ALL cases using
RT-PCR. Briefly, total RNA was extracted from cryopreserved
samples which contained more than 90% of blast cells (from
blood sample in six cases, from bone marrow in the remaining
17 cases) using Tri-reagent. RNA quality was assessed by
transillumination under UV after agarose electrophoresis. One
Table 1
No.
Children
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Adults
16
17
18
19
20
21
22
23
Hox11L2 expression in T-ALL
Hox11L2 expression was undetectable in the nine adult T-ALL
patients under study (Table 1). Conversely, blast cells from
nine of the 15 children analyzed expressed Hox11L2, as
Immunophenotype of 23 patients with T-ALL
Sex Age EGIL CD1a CD4 CD8 CD10 CD34 CD2 CD3 CD5 CD7 TCR␣␤ TCR␥␦ cCD3 cTCR␣␤ cTCR␥␦ Hox11L2
M
M
M
M
M
M
M
M
M
M
M
F
F
F
F
1.5
7
6
8
4
13
7
5
5
7
11
14
2
0.8
6
III
III
III
III
III
IV
III
III
II
II
IVb
III
IV
II
IVb
21
87
93
83
90
0
79
95
10
0
0
48
0
0
0
84
87
68
63
3
5
85
79
0
85
5
3
3
9
5
0
91
83
92
14
8
96
95
0
1
2
72
18
23
66
88
3
75
90
0
0
77
90
0
0
0
0
10
0
0
57
4
0
0
0
0
5
0
25
81
89
42
ND
ND
2
0
91
96
90
94
98
97
96
94
90
5
98
65
0
78
10
9
6
24
6
85
96
0
0
3
95
93
89
0
78
97
92
89
92
85
92
97
85
86
89
94
93
94
92
71
96
94
98
93
95
93
97
96
92
91
89
92
90
95
75
ND
5
5
ND
0
0
ND
0
ND
ND
7
14
ND
ND
5
ND
1
1
ND
0
0
ND
0
ND
ND
91
0
ND
ND
60
98
93
96
98
96
96
98
95
97
95
ND
98
ND
97
79
ND
34
57
0
ND
ND
0
59
ND
ND
ND
99
ND
ND
ND
ND
1
0
0
ND
ND
38
5
ND
ND
ND
0
ND
ND
ND
+
+
+
+
+
+
+
+
+
−
−
−
−
−
−
F
F
M
M
M
M
M
M
21
55
21
23
41
24
17
25
III
II
III
bi-P
III
III
NA
III
69
15
30
8
95
68
ND
72
4
1
7
2
86
1
34
2
4
84
2
38
97
16
56
96
6
0
93
60
96
47
ND
43
15
70
0
6
0
0
ND
0
15
2
1
6
96
2
97
96
8
2
1
21
0
7
87
82
77
94
93
74
96
99
96
72
83
94
95
80
81
96
95
96
ND
ND
ND
ND
ND
1
55
72
ND
ND
ND
ND
ND
0
0
0
50
95
91
89
24
98
ND
99
9
ND
ND
ND
ND
62
ND
84
0
ND
ND
ND
ND
0
ND
0
−
−
−
−
TdT, terminal deoxynucleotide transferase; cCD3 or cTCR, cytoplamic CD3 or TCR; NA, not applicable; ND, not done.
Leukemia
−
−
−
−
Hox11L2 expression in children T-ALL
L Mauvieux et al
shown for five patients in Figure 1. Sequencing of PCR products proved the correct amplification of Hox11L2 mRNA.
Hence, blast cells from 82% of boys in this short series (and
none of the four girls) displayed Hox11L2 expression.
In the five HOX11L2-positive children, in whom appropriate material was available for cytogenetic studies, no chromosomal abnormality was observed using conventional cytogenetic analysis (data not shown). Identification of a cryptic
t(5;14)(q35;q32) in three patients (patient Nos 2, 3, 7)9 correlated with Hox11L2 expression by RT-PCR, in contrast to
patient No. 8, in whom FISH (using BAC 45L16, BAC 546B8
and YAC885A6) and multi-FISH failed to detect the translocation.
In the control B-ALL group, Hox11L2 expression was undetectable in all three adults and 10 children studied (data not
shown), in agreement with the previously reported absence of
t(5;14)(q35;q32) by FISH analysis in 10 B-ALL cases.10
Immunophenotype
Proliferating cells from the T-ALL patients could be assigned
to subgroup T-II of the EGIL classification in five cases, T-III
in 13 cases and T-IV in three cases. Both T lymphocytic and
myeloid markers were displayed in one case (No. 23), which
was classified as bi-phenotypic. In another case (No. 22),
CD1a was not tested, and was not classified. Hence, not surprisingly,17 the subgroup T-III (which is defined by the
expression of CD1a regardless of the presence of other T cell
markers including membrane CD3) predominated (57% of
cases). In children (and not in adults), Hox11L2 expression
by RT-PCR correlated with that of CD1a (P = 0.04) and CD10
(P = 0.044) on the blast cell surface. In five of the nine cases
with Hox11L2 expression, the blast cells were double-positive
(DP) for CD4 and CD8 (Table 2). They expressed CD10 in
four of five cases and not CD34, which suggests that a differentiation arrest could have occurred at the DP stage (and earlier in patient No. 1 (CD34- and CD4-positive) and No. 5 and
No. 6 (double-negative (DN)). Altogether, staining for CD34
was (weakly) positive in two of nine patients with Hox11L2
expression and CD10 was detected in five of nine cases. Conversely, among patients with no detectable Hox11L2 mRNA,
Figure 1
RT-PCR analysis of HOX11L2 expression in T-ALL
samples. (a) a specific HOX11L2 fragment amplified from several
samples. H20: no template control. (b) Beta-actin control amplification.
staining for CD10 was consistently negative, no blast cells
were DP and CD34 was present in three of the four cases
studied for this marker (Table 2). None of the other T cell
markers was discriminative with respect to Hox11L2 positivity
(Table 1).
In adult patients, a common CD1a expression (by most cells
in four patients, half of them in one and a minority in the
other three patients studied) did not correlate with Hox11L2
expression (undetectable). CD10 was commonly detected and
the DP phenotype was rare. As in children, CD10 antigenpositive blast cells of adults were CD34 negative.
2419
Clinical evolution of children and HOX11L2
expression
All 15 children with T-ALL were included in EORTC protocols
and followed BFM treatments, except one infant patient (No.
14) who followed an infant pilot protocol. Six were classified
as intermediate risk, and nine as very high risk (VHR) following EORTC recommendations. HOX11L2 expression did not
correlate with age (Hox11L2-positive cases: median age 6
years, HOX11L2-negative cases: median age 6.5 years,
P = 0.90), nor white blood cell count at diagnosis (P = 0.688).
Two deaths were observed. One toxic death occurred in first
remission (case No. 3, Hox11L2 positive), and the other death
(case No. 13, Hox11L2 negative) occurred during first relapse,
1 year after autograft. All other patients are alive, and remain
in clinical remission. As depicted in Figure 2, survivals were
not significantly different in the two groups (P = 0.9, log-rank
test, median follow-up 25.5 months), in contrast with a previous report.18 Nevertheless, HOX11L2 expression strongly
correlated with male sex (P = 0.011, Fischer’s exact test), but
was not very different from the male to female ratio generally
observed in T-ALL (P ⬎ 0.05).
Discussion
We initially reported three cases of T-ALL with
t(5;14)(q35;q32) and expression of the developmental gene
Hox11L2.10 Hox11L2 belongs to a distinct family of orphan
homeobox genes including HOX11, HOX11L1 and
HOX11L2. These three genes harbor a threonine in the third
helix of the homeodomain, which confers specific DNA binding properties.19,20 Ectopic expression of HOX11 in T-ALL is
associated with translocations implicating TCR genes (t(10;14)
and t(7;10) for TCR ␣ and TCR ␤, respectively).6,20 In T-ALL
with t(5;14)(q35;q32), HOX11L2 expression is probably under
the influence of the CTIP2 (BCL11B) gene,10 located on chromosome 14, several hundreds of kilobases centromeric to the
main breakpoint area. The latter gene is strongly expressed in
the thymus,10 and is potentially implicated in T cell differentiation. CTIP2(BCL11B) is closely related to CTIP1 (BCL11A),21
and both are structurally related to the EVI9 oncogene.22 We
now extend our previous findings and show that blast cells
from nine of 15 children, all boys (82% of boys), and no adult
T-ALL patients expressed Hox11L2 at the mRNA level. In all
previously described cases, there was only one female with
T-ALL who expressed Hox11L2,10 suggesting a clear correlation with male sex, that remains unexplained. However, in
our series, sex ratio of HOX11L2-positive cases was not statistically different from that generally observed in T-ALL
(male/female = 3).18
Although FISH study could be performed only in a few
Leukemia
Hox11L2 expression in children T-ALL
L Mauvieux et al
2420
Table 2
Summary of children’s characteristics
No.
Sex
Age
WBC
(× 109/l)
CD1a
CD4/CD8
CD10
CD34
Hox11L2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
M
M
M
M
M
M
M
M
M
M
M
F
F
F
F
1.5
7
6
8
4
13
7
5
5
7
11
14
2
0.8
6
68
38
77
113
146
208
51
9
848
307
4
117
257
540
248
+
+
+
+
+
−
+
+
−
−
−
+
−
−
−
CD4SP
DP
DP
DP
DN
DN
DP
DP
DN
CD4SP
DN
CD8SP
(CD8)SP
(CD8)SP
CD8SP
+
−
+
+
−
−
+
+
−
−
−
−
−
−
−
+ −a
−
−
−
−
−
−
−
+ −a
+
+
+
ND
ND
−
+
+
+
+
+
+
+
+
+
−
−
−
−
−
−
FISH
+
+
+
−
−
a
Weakly positive.
WBC, white blood cells count at diagnosis; SP, single positive; DP, double positive; DN, double negative; (CD8), CD8 expression by a
minority of the cells.
Figure 2
patients.
Survival curves of HOX11L2-positive and -negative
cases, patient No. 8 illustrates the possibility of Hox11L2
expression in the absence of t(5;14)(q35;q32). Hox11L2
expression was confirmed in another sample of this patient’s
blast cells, and cytogenetic analysis was also confirmed in
several ways (5q35 BAC45L16, YAC885A6 and YAC546B8
FISH probes, multi-FISH (24 Xcyte probes, Metasysystems)
and IPM FISH (IRS-PCR DNA probes). Chromosome 5q35
interphase nuclei FISH (YAC 885A6, BAC45L16 and BAC
546B8) did not detect any translocation in this patient, and
no abnormality could be detected using conventional cytogenetics. Hence, Hox11L2 activation might occur independently of the t(5;14) translocation, as previously reported for
HOX11, possibly expressed without cytogenetically visible
rearrangements of chromosome 10.7,10 Another unknown
oncogenic event or submicroscopic abnormalities, different
from the cryptic t(5;14), might also occur in chromosome 5
(microdeletions, submicroscopic inversions) and lead to the
transcriptional activation of the gene. The second hypothesis
was documented for Tal-1 gene.3,23,24 Its deregulation resulted
from a cytogenetically undetectable interstitial deletion of
chromosome 1.25,26 Such discrete abnormalities might juxtapose Hox11L2 and potentially activate sequences, which may
Leukemia
be numerous in band 5q32, in view of the large number of
active genes in this genomic region. Ongoing molecular
characterization of chromosomal breakpoints may pinpoint
the mechanisms implicated in Hox11L2 expression.
In our series, neither t(5;14)(q35:q32) nor Hox11L2
expression was associated with other cytogenetic abnormalities. The high incidence of chromosomal deletions in T-ALL
(probably secondary abnormalities) suggests that previously
published cases displaying a chromosomal deletion may
harbor the cryptic t(5;14)(q35:q32). We observed a correlation
between Hox11L2 gene activation and CD1a (and usually
CD10) expression, and an inverse one with CD34. Although
the number of patients under study is small, it is quite striking
that blast cells from the only two boys in whom Hox11L2
mRNA was undetectable carried CD34, as this is not expected
in T-ALL.27 This is in agreement with previous reports on an
inverse correlation between CD34 and CD10 in T-ALL.28 In
the normal pediatric thymus, the expression of CD1a and
CD10 increases concomitantly with the loss of CD34 during
thymocyte maturation.29 Physiologically, CD1a expression is
restricted to cortical thymocytes, where TCR rearrangements
take place. Illegitimate rearrangements in CD34−CD1a+
CD10+ DP thymocytes may juxtapose Hox11L2 and activating
sequences, leading to T-ALL. Cloning of chromosomal breakpoints is required to search for an implication of recombinasespecific sequences in the translocation process.
If HOX11L2 expression correlated strongly with male sex,
no association was observed with age, white blood cell count
at diagnosis and, more importantly, with outcome. These
observations contrast with previous reports,18 where
HOX11L2 expression was associated with poor survival.
Moreover, incidence of HOX11L2 expression was lower in
this study. These discrepancies may be explained by the age
of the patients (not detailed in Ref 18), and the different therapeutic protocol used. In our study, 13/15 children are alive in
clinical remission, without any relapse. These therapeutic
results prevent any statistically relevant observation about the
HOX11L2 role in clinical outcome.
From a practical point of view, the finding of DP CD1a and
CD10-positive blast cells appears to be predictive of Hox11L2
expression in childhood T-ALL. Further studies are necessary
Hox11L2 expression in children T-ALL
L Mauvieux et al
to evaluate the respective incidence of t(5;14)(q35;q32) and
Hox11L2 expressions, which appear to occur independently
in certain cases. It will require the use of several methods.
Indeed, spectral karyotypic analysis of a T-ALL series failed to
detect the cryptic t(5;14)(q35;q32) in childhood T-ALL.30 It is
worth mentioning that HOX11L2 was not represented on the
microarrays used in T-ALL studies,18,31–33 stressing the limits of
microarray diagnostic strategies. Cytogenetic, molecular and
immunological studies should be combined in larger series,
in order to confirm the correlation between cytogenetic
abnormalities, phenotype and Hox11L2 expression, and to
specify its prognostic significance.
Acknowledgements
We thank J-L Preud’homme for critical reading of the manuscript, M-P Gaub for providing material for B-ALL patients, JP Bergerat for adult patients material, D Cherif and J AurichCosta for providing IPM-FISH chromosomal probes.
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