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.
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 TCRα/δ or TCRβ,4,5 t(10;14)(q24;q11), in which the homeoprotein gene Hox11 is placed under the control of the TCRα/δ 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, 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
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).
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 μg/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 Alu-PCR, 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 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
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 (pro-T 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
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 μg 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 β-actin primers (UA 5′-ATCATGTTTGAGACCTTCAA-3′, AL 5′-CATCTCTTGCTCGAAGTCCA-3′).
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).
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 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
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, 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 antigen-positive blast cells of adults were CD34 negative.
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).
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 α and TCR β, 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 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 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 recombinase-specific 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 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,18,31,32,33 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.
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We thank J-L Preud'homme for critical reading of the manuscript, M-P Gaub for providing material for B-ALL patients, J-P Bergerat for adult patients material, D Cherif and J Aurich-Costa for providing IPM-FISH chromosomal probes.
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Mauvieux, L., Leymarie, V., Helias, C. et al. High incidence of Hox11L2 expression in children with T-ALL. Leukemia 16, 2417–2422 (2002). https://doi.org/10.1038/sj.leu.2402709
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