Original Article

Leukemia (2006) 20, 1238–1244. doi:10.1038/sj.leu.2404243; published online 4 May 2006

Molecular cytogenetic study of 126 unselected T-ALL cases reveals high incidence of TCRbold italic beta locus rearrangements and putative new T-cell oncogenes

B Cauwelier1, N Dastugue2, J Cools3,4, B Poppe1, C Herens5, A De Paepe1, A Hagemeijer3 and F Speleman1

  1. 1Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
  2. 2Laboratoire d'Hématologie, Hôpital Purpan, Toulouse, France
  3. 3Center for Human Genetics, University of Leuven, Leuven, Belgium
  4. 4Flanders Interuniversity Institute for Biotechnology (VIB), University of Leuven, Leuven, Belgium
  5. 5CHU Sart Tilman, Université de Liège, Liège, Belgium

Correspondence: Dr B Cauwelier, Center for Medical Genetics, Medical Research Building, Room 120.024, Ghent University Hospital, Ghent, 9000 Belgium. E-mail: Barbara.Cauwelier@UGent.be

Received 10 November 2005; Revised 13 March 2006; Accepted 24 March 2006; Published online 4 May 2006.

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Abstract

Chromosomal aberrations of T-cell receptor (TCR) gene loci often involve the TCRalphadelta (14q11) locus and affect various known T-cell oncogenes. A systematic fluorescent in situ hybridization (FISH) screening for the detection of chromosomal aberrations involving the TCR loci, TCRalphadelta (14q11), TCRbeta (7q34) and TCRitalic gamma (7p14), has not been conducted so far. Therefore, we initiated a screening of 126 T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma cases and 19 T-ALL cell lines using FISH break-apart assays for the different TCR loci. Genomic rearrangements of the TCRbeta locus were detected in 24/126 cases (19%), most of which (58.3%) were not detected upon banding analysis. Breakpoints in the TCRalphadelta locus were detected in 22/126 cases (17.4%), whereas standard cytogenetics only detected 14 of these 22 cases. Cryptic TCRalphadelta/TCRbeta chromosome aberrations were thus observed in 22 of 126 cases (17.4%). Some of these chromosome aberrations target new putative T-cell oncogenes at chromosome 11q24, 20p12 and 6q22. Five patients and one cell line carried chromosomal rearrangements affecting both TCRbeta and TCRalphadelta loci. In conclusion, this study presents the first inventory of chromosomal rearrangements of TCR loci in T-ALL, revealing an unexpected high number of cryptic chromosomal rearrangements of the TCRbeta locus and further broadening the spectrum of genes putatively implicated in T-cell oncogenesis.

Keywords:

T-ALL, cytogenetics, TCR rearrangements, HOXA

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Introduction

T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LL) are lymphoid malignancies representing a heterogeneous group of diseases that vary with respect to morphological, cytogenetic and immunologic features of the T-lymphoblasts.1 The discovery of chromosomal rearrangements in these disorders has been pivotal in the identification of the genes involved in T-ALL development and normal thymocyte differentiation.2, 3 In most instances, these chromosomal aberrations are translocations that preferentially involve the T-cell receptor TCRalphadelta locus (14q11) and to a much lesser extent the TCRbeta locus (7q34) and affect a wide array of genes with oncogenic properties 1p32(TAL1), 1p34(LCK), 8q24(MYC), 9q34(TAL2), 9q34(TAN1/NOTCH1), 10q24 (HOX11), 11p13(RBTN2/LMO2), 11p15(RBTN1/LMO1), 14q32(TCL1), 19p13(LYL1), 21q22(BHLHB1) and Xq28 (MTCP1).3, 4, 5, 6 Translocations affecting TCR genes largely result in deregulated expression of proto-oncogenes by juxtaposing promoter and enhancer elements of TCR genes in the proximity of these developmentally important genes.7 Interestingly, further molecular studies revealed that some of these genes (TAL1, HOX11, NOTCH1) were functionally activated in a much higher frequency than expected from a cytogenetic point of view,8, 9, 10 further underlining the importance of the original cytogenetic investigations. Also, biallelic expression has been reported in about half of the cases with TAL1, LMO2 and HOX11 expression pointing at disturbance of an upstream regulatory control mechanism.11 In contrast to B-ALL, in which predominantly chimeric transcription factor proteins are generated, gene fusions occur in a much lower rate in T-ALL (predominantly MLL/ENL and CALM/AF10).12, 13, 14

Recently, the spectrum of chromosomal abnormalities in T-ALL has been further widened by the finding of new recurrent but cryptic alterations. First, a cytogenetically undetectable translocation t(5;14)(q35;q32) was found in about 20% of childhood T-ALL juxtaposing the HOX11L2 gene (5q35) to the distal region of the BCL11B gene.5 A further remarkable finding was the extrachromosomal (episomal) amplification of NUP214-ABL1 fusion genes in 6% of T-ALL cases leading to constitutively phosphorylated tyrosine kinase activity, which can be inhibited upon addition of imatinib, a selective inhibitor of ABL1 kinase activity.10, 15, 16 Recently, we observed yet another recurrent chromosomal rearrangement, that is, an inv(7)(p15q34) in a subset of T-ALLs. This rearrangement juxtaposes the distal part of the HOXA gene cluster on 7p15 to the TCRbeta locus on 7q34 and causes increased HOXA10 and HOXA11 expression levels.17 The occurrence of this inv(7) as well as a t(7;7)(p15;q34) was subsequently also demonstrated by Soulier et al.18 Interestingly, upregulated HOXA gene expression was also found in MLL-ENL and CALM-AF10-positive T-ALLs, thus pointing at a more general role of HOXA genes in T-cell oncogenesis.19, 20

These observations thus indicate that a plethora of genes can be implicated in the development of T-ALL as a result of various recurrent chromosomal changes, many of which remained undetected upon cytogenetic investigation until recently. In particular, the finding of a cryptic t(7;11)(q34;q24) involving the TCRbeta locus (7q34) in a childhood T-ALL case21 and the new recurrent inv(7)(p15q34) triggered the screening for additional cryptic TCR rearrangements in a cohort of 126 T-ALL patients and 19 T-ALL cell lines. Our findings show that the majority of TCRbeta chromosomal rearrangements remained undetected upon routine karyotyping and that new T-cell oncogenes may be implicated in some of these cases (Figure 1).

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Fluorescent in situ hybridization analysis in patient no. 23 carrying a reciprocal TCRbeta-TCRalphadelta chromosomal rearrangement. T-cell receptorbeta flanking BACs are labeled in Spectrum Green (white) and TCRalphadelta flanking BACs in Spectrum Orange (black).

Full figure and legend (45K)

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Materials and methods

Patients and controls

Cytogenetic cell suspensions or unstained slides from 126 diagnostic T-ALL (n=109) and T-LL (n=17) samples were collected retrospectively from cytogenetic centers between 1988 and 2005. Diagnosis of T-ALL/LL was made according to the morphological and cytochemical criteria of the French–American–British classification22 and by imunophenotyping. The selection of cases was based on the availability of fixed cell suspension or unstained slides, which permit fluorescent in situ hybridization (FISH) investigation. Molecular data and immunophenotype were available only for most recent cases and are not shown. This cohort of T-ALL and T-LL cases included 80 children and 46 adults.

The 19 T-ALL cell lines were purchased from DSMZ (http://www.dsmz.de, Braunschweig, Germany). Peripheral blood lymphocytes from healthy donors with normal karyotypes served as negative controls for validation and cutoff level determination of the different FISH assays. Cell suspensions from T-ALL cases or cell lines with cytogenetically proven breakpoints at the different known T-cell oncogenes (LCK, MYC, HOX11, LMO2, LMO1, NOTCH1) were used as positive controls.

Methods

Cytogenetic analysis
 

Diagnostic specimens (bone marrow, blood and pleural fluid) and cell lines were cultured and harvested for cytogenetic analysis according to established methods. Chromosome slides were G or R banded. Chromosome aberrations are described according to guidelines of an International System for Human Cytogenetic Nomenclature (ISCN 1995).23

Clone selection and validation
 

RPCI-11 (Human BAC Library) clones were selected using the bioinformatics resources available at National Center for Biological Information (http://genome.ucsc.edu) and Ensembl Genome Browser (http://www.ensembl.org/). Clones were provided by the Welcome Trust Sanger Institute (Cambridge, UK) and Invitrogen (Paisley, Scotland).

Disruption of the TCR loci was assessed by dual color FISH with TCR flanking probes. Clones for the TCRalphadelta, TCRbeta and TCRitalic gamma applied in the present study are listed in Table 1. Additional FISH probes used to confirm the involvement of TCR partner genes in cases carrying TCRbeta and/or TCRalphadelta chromosomal rearrangement (identified by a split signal of the flanking probes) are listed in Table 1, with the exception of MYC for which we applied the LSI MYC Dual Color, Break Apart Rearrangement Probe (Vysis, Abbott, Ottignies, Belgium). DNA isolation of bacterial artificial chromosome (BAC) clones and FISH was performed as described previously.24 Subsequently, large-scale DNA amplification was performed using the GenomiPhi Amplification Kit (Amersham Biosciences, Roosendaal, The Netherlands), which utilizes bacteriophage Phi29DNA polymerase and exponentially amplifies single- or double-stranded linear DNA templates during an isothermal (30°C), strand displacement reaction.25 Phi-amplified DNA was labeled as described previously24 using spectrum green- and spectrum orange-dUTP (SG-dUTP and SO-dUTP, Vysis, Abbott).


Validation of BAC clone genomic positions of TCRalphadelta, TCRbeta and TCRitalic gamma flanking clones was performed using STS (sequence tagged site) PCR with two STS genomic markers per BAC clone.

Using this approach, the genomic positions of the different TCR gene loci provided by the bioinformatics resources were confirmed.

Determination of cutoff levels
 

Determination of cutoff levels of these new probe sets was performed by counting 200 nuclei in five negative controls (peripheral blood lymphocytes from healthy donors) for each probe set.

Based on the results in negative controls, a split was defined as a spatial separation of the flanking probes of more than three times the estimated signal diameter.26

Using these criteria, the cutoff levels of the different probe combinations were 6% for TCRalphadelta, 6.5% for TCRbeta and 2% for TCRitalic gamma.

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Results

A total of 126 T-ALL/LL cases and 19 T-ALL cell lines were investigated. Karyotypic analysis was successful in 119 cases, whereas seven cases did not yield metaphases. Clonal abnormalities were present in a high percentage of cases (74.7%:89/119) (data not shown), which can be biased by the selection of patient samples with possibly higher white blood cell counts at presentation. Fluorescent in situ hybridization screening for TCR rearrangements using dual color break apart assays showed TCRalphadelta rearrangements in 22/126 patients (17.4%) in keeping with data from the literature, a surprisingly similar high number of patients (24/126, 19%) with TCRbeta aberrations and no TCRitalic gamma rearrangements. Split signals with the specific probe sets were observed in 15–95% of cells for TCRalphadelta and in 20–98% for TCRbeta. Simultaneous rearrangements targeting both the TCRbeta and TCRalphadelta genes were observed in six patients and in one T-ALL cell line (SUP-TI).

Translocations affecting the TCRbeta locus in T-cell acute lymphoblastic leukemia

Fluorescent in situ hybridization screening for TCRbeta chromosomal rearrangements yielded split signals for the TCRbeta locus in 24 cases (19%: 24/126) (Tables 2 and 4); these included three T-LL and 21 T-ALL. In 19 of these 24 positive cases, involvement of a known recurrent TCRbeta partner gene could be confirmed by FISH with the appropriate probes (Table 1): TAL1 (case no. 2), HOXA (case nos. 15–22), HOX11 (case nos. 3,4–8–14–20), LMO2 (case no. 7), LMO1 (cases nos. 9 and 10), TCRalphadelta (case nos. 13–23) and NOTCH1 (case no. 12). HOXA gene expression levels were reported previously for case nos. 15–19. In the additional cases 21 and 22 detected by FISH screening, a similar pattern of increased HOXA10 and HOXA11 was observed (details will be published elsewhere). Owing to poor quality and/or paucity of metaphases, the partner chromosome remained undetermined in the remaining five cases showing TCRbeta rearrangement. These rearrangements were slightly more frequent in adults compared to children, 14/80 children (17.5%) versus 10/46 adults (21.7%). One patient (case no. 1) showed rearrangement of the TCRbeta locus with an as yet unidentified partner gene on chromosome 11q24. Further analysis to identify this new partner gene is ongoing and will be reported elsewhere.



Abnormal karyotypes were found in 16 out of 24 TCRbeta-positive cases (Table 2), whereas translocations affecting the 7q34 locus were detected in only four of 24 cases. Partial deletions of chromosome 7q or 7p were detected in three cases and two cases showed additional material on 7q. Taken together, TCRbeta genomic rearrangement was unsuspected from cytogenetic analysis in as much as 14 of 24 (58.3%) cases when excluding failures. Two out of 19 cell lines screened with the TCRbeta flanking probes showed genomic rearrangement of this locus with LCK (T-ALL cell line HSB2) and NOTCH1 (T-ALL cell line SUP-TI) as partner genes (Table 2).

Translocations affecting the TCRalphadelta locus in T-cell acute lymphoblastic leukemia

Translocations involving the TCRalphadelta locus were detected in approximately the same number of patients as for TCRbeta, that is, 22/126 (17.4%) cases (Tables 2 and 4) and mostly included T-ALL (n=21). However, involvement of known T-cell oncogenes was confirmed in only 12 of 22 rearranged cases. Unexpectedly, one TCRalphadelta rearranged case (no. 23) showed a balanced rearrangement with the TCRbeta locus, which brings the total number of identified TCRalphadelta partner genes to 13 out of 22. These findings suggest that many of these rearrangements targeted unknown T-cell oncogenes. Within the TCRalphadelta rearranged group involving known T-cell oncogenes, HOX11 was most frequently involved followed by LMO2, TAL1 and MYC, which involved two cases each. TCL1, HOXA and TCRbeta were detected in single cases. For the remaining nine cases carrying a TCRalphadelta rearrangement, partner genes could not be identified. Interestingly, TCRalphadelta rearrangements showed involvement of an unknown partner gene on chromosome 6q22 (case no. 40) and 20p12 (case no. 41) (Table 2). Of the 19 cell lines screened with TCRalphadelta flanking clones, five showed rearrangements with partner genes LMO1 (RPMI 8402), LMO2 (TALL 104), MYC (MOLT16 and KE-37), HOX11 (ALL-SIL) and an unidentified gene (SUP-TI). In contrast to TCRbeta rearrangements, TCRalphadelta rearrangements were more frequent in children (16/80; 20%) versus adult T-ALL patients (6/46: 13%).

In this group of TCRalphadelta rearranged cases (n=22), abnormal karyotypes were present in 19 patients (Table 2). Of these, translocations involving the TCRalphadelta locus were obvious from banding analysis in only 12 of these 19 patients. In seven cases with clonal karyotypes, no 14q11 rearrangement was apparent, indicating that at least 30% (7/22) of TCRalphadelta-positive cases in this series was cryptic. This could be explained in one of these cases through the presence of complex abnormalities. This case (no. 28) showed two subclones carrying rearrangement of chromosome 14 at different chromosome bands. One subclone carried a rearrangement of chromosome 14 at the approx14q32 band (IgH locus) and was translocated to the long arm of chromosome 20,24 revealing a t(14;20)(q32;q12). In another subclone, chromosome 14 showed disruption of the TCRalphadelta locus (14q11) with inversion of the distal probe to the short arm of chromosome 14 thus revealing a new inv(14)(p?q11).

Simultaneous occurrence of TCRbeta and TCRalphadelta genomic rearrangements

Five T-ALL patients (cases nos. 1, 6, 10, 13, 23) and one T-ALL cell line (SUP-TI) carried genomic rearrangements of both TCRbeta and TCRalphadelta loci. In four of these patients, both TCR genes targeted different T-cell oncogenes (Table 2) as confirmed by FISH with the appropriate probes. Unexpectedly, patient nos. 13 and 23 showed a rearrangement between the TCRbeta and TCRalphadelta gene loci, unbalanced in case no. 13 and balanced in patient no. 23. Five of these patients were children, possibly reflecting the higher susceptibility to genomic rearrangements involving TCR loci during childhood.

Previously unreported chromosome aberrations in T-cell acute lymphoblastic leukemia

Chromosome aberrations found in this series, which have not been reported previously in T-ALL, are listed in Table 3. Fluorescent in situ hybridization investigation for oncogenes known to be involved in leukemogenesis (LMO1, LMO2, HOX11, HOXA, ETV6, NUP98) were applied and in most cases turned out to be negative, indicating that a large set of putative T-cell oncogenes still remains undiscovered.


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Discussion

Here we report the results of a comprehensive FISH screening performed in 109 T-ALL, 17 T-LL and 19 T-ALL cell lines using TCR flanking FISH probes to determine the incidence of chromosomal rearrangements involving the TCR genomic loci TCRalphadelta (14q11), TCRbeta (7q34) and TCRitalic gamma (7p15). This approach allowed us to demonstrate for the first time that TCRbeta rearrangements occur in a similarly high frequency as TCRalphadelta rearrangements, that is, in 19% of T-ALL patients. Of further importance, we showed that as much as half (14/24) of the TCRbeta and about one-third (8/22) of the TCRalphadelta rearrangements were not detected upon karyotypic analysis. Our study thus indicates that using standard karyotyping, chromosomal rearrangements involving T-cell receptors (in particular TCRbeta) have been significantly underestimated so far.27 In line with previous reports, no TCRitalic gamma aberrations were observed in this series. Apparently, these TCRitalic gamma rearrangements are confined to T-cell tumors in patients with ataxia telangiectasia (ATM) where these rearrangements are frequently found.28 The frequency and age distribution of TCRalphadelta rearrangements in our study are in line with the series reported by Heerema et al.,29 whereas other larger studies of adult T-ALL found that the frequency of TCRalphadelta rearrangements was much higher in adults compared to childhood T-ALL.30, 31 For patients showing a TCRbeta locus rearrangement, conventional karyotyping showed aberrations in only 3.1%, which is somewhat in between previous cytogenetic reports of 7q34 abnormalities in adult (7.5%)27 and childhood (1%)30 T-ALL. The incidence of TCR rearrangements (TCRbeta and/or TCRalphadelta) was slightly higher in the T-ALL group, which was possibly biased by the much larger number of patients with T-ALL compared to T-LL. In the T-LL subgroup, 4/17 (23.5%) were positive for a TCR rearrangement, whereas 36/109 (33%) T-ALL showed one of these rearrangements.

The high incidence of cytogenetically undetected TCRbeta (14 out of 24 TCRbeta-positive cases) and TCRalphadelta (eight out of 22 TCRalphadelta-positive cases) rearrangements is remarkable. For TCRbeta rearrangements, eight of 14 cytogenetically undetected cases showed other clonal rearrangements and re-evaluation of the karyotypes allowed us to detect the TCRbeta aberration in two cases (nos. 3 and 4). This could be explained by the distal localization of the TCRbeta locus (7q34) together with a distal chromosomal position of the breakpoints of the TCRbeta partner genes, that is, t(7;11)(q34;q24), t(7;10)(q34;q24) and inv(7)(p15q34). In two cases (nos. 7 and 8) only normal metaphases were found at diagnosis and re-evaluation of karyotypes did not show the aberration, suggesting that only non-leukemic cells were cultured. This explanation is not valid for the TCRalphadelta locus rearrangements, which should be readily detectable on G-banding analysis. For TCRalphadelta rearrangements that remained undetected upon karyotyping, two were presented as a marker chromosome (case nos. 13–28), one resulted form a complex rearrangement (case no. 28) and a third (case no. 26) was not detected as probably only normal cells were karyotyped. Re-evaluation of case no. 26 remained negative. Interestingly, for the remaining TCRalphadelta-positive cases that remained undetected, chromosomal rearrangements were found in karyotypically abnormal cells (case nos. 32, 33, 35, 37) raising the question that these represent true cryptic rearrangements.

Preferential partner genes for TCRbeta in our series include HOXA (7p15)17 and HOX11 (10q24), which were involved in seven and four cases, respectively. Recently, HOXA cluster genes were shown to be involved in a chromosomal rearrangement with the TCRalphadelta (14q11) locus in a T-ALL patient (case no. 30) carrying a t(7;14)(p15;q11) (unpublished observation).

The finding that in 14 TCRalphadelta or TCRbeta chromosomal rearrangements the partner gene could not be identified after testing of all genes known to be implicated in T-ALL is of great potential importance. Also, two new translocations involving the TCRalphadelta locus were found in this series, that is, t(6;14)(q22;q11) (case no. 40) and t(14;20)(q11;p12) (case no. 41) (Table 2). Further efforts to identify these putative new partner genes are ongoing. Recently, a new translocation, that is, t(7;11)(q34;q24)21 affecting the TCRbeta locus and an as yet unidentified partner gene on chromosome 11q24 was described (case no. 1 in Table 3) and is analyzed further. Other chromosomal aberrations not reported previously in T-ALL (Table 2) include three cases with rearrangements of chromosome 9p21–24. This is the region harboring the CDKN2A (encoding p14 and p16 proteins) and CDKN2B (encoding p15 protein) tumor suppressor genes, which are the primary targets of 9p21 deletions in T-ALL and have been described to be present in 65% of T-ALLs.32, 33 Translocations affecting this gene locus have been reported in ALL but mostly in B-ALL.30, 34, 35 Interestingly, two of these patients carrying a rearrangement of 9p also showed a homozygous deletion of p16.

An interesting observation is the presence of rearrangements of both TCRalphadelta and TCRbeta loci in six patients and one cell line. Five of these patients were children, possibly reflecting the higher susceptibility for errors in VDJ recombination as a consequence of greater antigen exposure during childhood. In four patients, involvement of different T-cell oncogenes by both TCRbeta and TCRalphadelta genes was confirmed using FISH with the appropriate flanking BAC clones. No preferential involvement of a particular gene seems evident from this small series, but it should be noted that four of the 12 partner genes in these cases remained unidentified. Interestingly, two patients (case nos. 13 and 23) carried a translocation between the two TCR loci: TCRbeta (7q34) and TCRalphadelta (14q11); unbalanced in case no. 13 and balanced in case no. 23. So far, rearrangements between two TCR loci, TCRitalic gamma (7p15) and TCRalphadelta (14q11), have been reported in a high frequency in patients with ATM.28 However, this aberration has also been found at very low frequencies in T-lymphocytes from healthy individuals.36 These observations raise the possibility that rearrangements affecting both TCR loci are not merely chromosomal aberrations associated with tumorigenesis, but could represent the capacity of the recombinase system to generate additional immune diversity.37

In the light of the present findings, we would recommend thorough cytogenetic and molecular cytogenetic screening for cases included in ongoing and future gene expression profiling studies in T-ALL. This information may be critically important in the data analysis and delineation of genetic subgroups. Also, it will broaden our understanding of the various genetic mechanisms that lead to unscheduled activation or sustained expression of the plethora of genes implicated in T-cell oncogenesis.

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Acknowledgements

This study was supported by the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Grants Nos. G.0310.01 and G.0106.05, and GOA, Grant No. 12051203. This text presents research results of the Belgian program of Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Science Policy Programming. The scientific responsibility is assumed by the authors. BC is supported by the Belgian program of Interuniversity Poles of Attraction. We are thankful to Betty Emanuel and Nurten Yigit for excellent technical assistance.