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The Cardiac Homeobox Gene NKX2-5 Is Deregulated by Juxtaposition with BCL11B in Pediatric T-ALL Cell Lines via a Novel t(5;14)(q35.1;q32.2)¹

DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen), Department of Human and Animal Cell Cultures, 38124 Braunschweig, Germany [S. N., M. K., H. G. D., R. A. F. M.]

	ABSTRACT

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A cryptic chromosome rearrangement, t(5;14)(q35.1;q32.2), recently identified in pediatric acute lymphoblastic leukemia (ALL), targets activation of TLX3 at 5q35.1 by juxtaposition with a region downstream of BCL11B at 14q32.2. We describe a novel variant t(5;14) whereby NKX2–5, a related (NK-like family) homeobox gene located 2 Mb telomeric of TLX3, juxtaposes BCL11B in a subset of T-cell ALL cell lines. In this t(5;14) variant, NKX2–5 is expressed instead of TLX3 at both RNA and protein levels. Subsequent expression screening failed to detect involvement of additional NK-like genes in T-cell ALL cells. Our data pinpoint a regulatory region far downstream of BCL11B effecting ectopic homeobox gene activation. This study also identifies in vitro models for both t(5;14) variants and raises questions about diagnostic fluorescence in situ hybridization/reverse transcription-PCR screening in ALL.

	INTRODUCTION

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Recurrent but cryptic chromosome changes in leukemia are increasingly being identified by FISH.³ A recent example is t(5;14)(q35.1;q32.2) present in 20% of children with T-ALL (1, 2, 3) . Formation of t(5;14) is believed to target deregulation of a homeodomain gene TLX3 (also called HOX11L2) at 5q35.1 via its juxtaposition with the distal region of a krueppel-like zinc-finger transcription factor BCL11B (also called CTIP2) at 14q32.2, which is preferentially expressed in T cells (1 , 4 , 5) . TLX3 belongs to the NK-like family of homeobox genes (6) , which also includes TLX1 located at 10q24 and is involved in at least two leukemic translocations in T-ALL, t(7;10)(q35;q24) and t(10;14)(q24;q11.2), effecting its juxtaposition with TRB@ and TRD@, respectively. Extending this paradigm, Hansen-Hagge et al. (7) have described two adult ALL patients with t(5;14)(q35;q11.2) with breakpoints upstream of TLX3 and within TRD@. Although the leukemic involvement of homeobox genes is known, the role of BCL11B remains unclear, although its close homologue, BCL11A, expressed in B cells and derived malignancies, is cast as a dominant oncogene (4) . While screening T-ALL cell lines by FISH, we found examples with t(5;14) in which the 5q35 breakpoints outlay TLX3. We describe the characterization of these cell lines to reveal an alternative homeobox gene target of t(5;14) showing that the downstream region of BCL11B is capable of activating at least two NK-like homeobox genes.

	MATERIALS AND METHODS

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Cell Lines.
CCRF-CEM was established in 1964 from a 3-year-old female with relapsing T-ALL. PEER was established in 1977 from a 4-year-old female at second relapse of T-ALL. CCRF-CEM and PEER exhibit immature imunophenotypes, being classed T-III cortical/T-cell receptor ß+ and T-IV/T-cell receptor +, respectively. Details of these and other cell lines used in this study and obtained from the DSMZ⁴ are given in Drexler (8) . DNA profiling has shown that the purportedly independent cell lines, MKB-1 and BE-13, are early passage divergent subclones of CCRF-CEM and PEER, respectively (9) .

Cytogenetic Analysis.
Harvesting, slide preparation, trypsin G-banding (GTG), and FISH were performed as described (10) . BAC clones were obtained from BAC/PAC Resources (Oakland, CA), RZPD (Berlin, Germany), The Sanger Centre (Cambridge, England), J. Flint (Oxford, England), J.W.G. Janssen (Heidelberg, Germany), and R. Siebert (Kiel, Germany). Clone DNA was prepared using commercial kits (Qiagen, Hilden, Germany) and labeled by nick translation (Invitrogen, Karlsruhe, Germany). FISH images were analyzed using commercial software (Applied Imaging, Newcastle, United Kingdom).

Analysis of Gene Expression.
For RT-PCR, cDNA was synthesized from 5 µg of total RNA extracted from 2 x 10⁶ cells with TRIzol (Invitrogen) by random priming in 20 µl using Superscript II (Invitrogen). Three microliters of cDNA template were amplified by PCR in 25 µl and checked using UBTF primers (Table 1) . Incubation steps were as follows: 1 min/94°C, 30 s/55°C (for deviations, see Table 1 ) and 3 min/72°C for 35 cycles using a thermal cycler (Perkin-Elmer, Wiesbaden, Germany). PCR products were analyzed on 1.5% agarose gels and cloned in pGEM-Teasy (Promega, Madison, WI) for sequencing (MWG Biotech, Ebersberg, Germany). For Northern analysis, 10 µg of total RNA were loaded onto agarose gel, transferred onto nylon membranes (Roche, Mannheim, Germany), and UV cross-linked (Stratagene, Heidelberg, Germany). Full-length cDNA probes of hamster ß-actin (1200 bp) and NKX2–5, generated by RT-PCR (Table 1) , were random primed labeled with ³²P (Stratagene). Detection was performed by phosphoimaging (Storm, Krefeld, Germany). For Western analysis, 4 x 10⁶ cells were lysed with 50 µl of RIPA-buffer, 1 µl of aprotinin (1 mg/ml), 5 µl of phenylmethylsulfonyl fluoride (20 ng/ml), and 50 µl of 2 x SDS buffer. Lysates (20 µl) were loaded onto 15% SDS-PAGE gels (Bio-Rad, Munich, Germany) and blotted onto nitrocellulose membranes (Schleicher Schuell, Dassel, Germany) by the semidry method. Detection of -NKX2–5 (H-114) and -TLX1 (C-18; Santa Cruz Biotechnology, Heidelberg, Germany) used a Western lighting kit (Perkin-Elmer). Protein loading equivalence was checked using Ponceau dye.

	RESULTS

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View larger version (57K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. FISH analysis of t(5;14)(q35.1;q32.2). A and B, G-banded karyotypes of CCRF-CEM and PEER cell lines, respectively. Both partners of the cryptic t(5;14) are indistinguishable from their normal homologues (arrows). However, PEER carries a simultaneous deletion of q22-q31 on the der (5)t(5;14). Both cell lines carry additional secondary changes. FISH image (C) shows the results of hybridizing a CCRF-CEM metaphase with painting probes for chromosomes 5 (red) and 14 (yellow). Note the absence of any visible rearrangement. D and E, analysis of the breakpoints at NKX2-5 and 3'-BCL11B. In CCRF-CEM (D), split BAC FISH signals show 5q35 breakpoints at NKX2-5 (yellow), whereas the presence of green signal only on the der (5) shows the 14q32 breakpoint occurred between 2177F13 and 1057P17. In PEER (E), the presence of signal on the der (14) from 466H21 (green) without signals from flanking centromeric (red) or telomeric (yellow) clones documents the mini-insertion of NKX2-5 material. Note the weaker green signal on the der (5) attributable to the centromeric breakpoint within 466H21. Metaphase spreads were hybridized with contrasting BAC/PAC clones labeled with Spectrum Red-dUTP, Spectrum Green-dUTP, or Cy3-dUTP. Chromosomes were counterstained with DAPI, and images were captured and analyzed using special software (Applied Imaging). A diagrammatic representation of BAC/PAC clones referred to in this study is shown in F. The top and bottom parts depict 5q35 and 14q32 breakpoints in CCRF-CEM, PEER, and HPB-ALL cell lines (arrowheads), relative to those described by Bernard et al. (1; arrows) and to their putative gene targets. Clones straddling (split-signal), or immediately flanking breakpoints, are shaded darkly. Breakpoints were inferred by mapping to overlapping split-signal clones. Contrast the clustering of 5q35 breakpoints at 5'-NKX2-5 and 5'-TLX3 with the scattering of 14q32 breakpoints over 3'-BCL11B. The cytogenetic data pinpoint the putative enhancer to the far downstream region of BCL11B, centromeric of the breakpoint in PEER.

View larger version (57K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Gene expression analysis. A, the results of RT-PCR analysis. PEER showed expression of BNIP1, NKX2–5, and TLX1, whereas BCL11B, RANBP17, and TLX3 were negative. CCRF-CEM was positive for BCL11B, BNIP1, and NKX2–5 but negative for RANBP17 and TLX3. UBTF expression served as a cDNA control. The results of Northern analysis of NKX2–5 are shown in B. At least two signals (arrows) at 1.8 and 3.6 kb were visible using the NKX2–5 probe. Total RNA from HPB-ALL, CCRF-CEM, and PEER was separated on agarose gel (left). The blot was hybridized with 32P-labeled probes for actin (middle) and NKX2–5 (right). The image in C illustrates the detection of NKX2–5 by Western blot. Two bands at Mr 35,000 and 37,000 (arrows) are visible in PEER, CCRF-CEM, and 293. In HELA, only one band was detected (at Mr 35,000), whereas in HPB-ALL, no signals were observed. The detection of TLX1 by Western blot is depicted in D. In contrast to HPB-ALL, CCRF-CEM, and PEER, ALL-SIL shows a protein band at Mr 35,000 (arrow). Thus, transcription of TLX1 in PEER proceeded without translation. Alternative splicing of BCL11B (shown in E) was analyzed by RT-PCR using specific primers for variant 1 (middle) or variant 2 (bottom). Excepting PEER, all cell lines shown expressed BCL11B variant 2 (arrow). Variant 1 was expressed in cell lines with t(5;14)(q35.1;q32.2): BE-13, CCRF-CEM, HPB-ALL, and MKB1 (arrow). Both variants were expressed in the peripheral blood of a healthy donor. cDNA quality was checked using primers for UBTF (top gel).

Analysis of Genes Located in the Breakpoint Region at 14q32.
Unlike the 5q35.1 breakpoints in CCRF-CEM and PEER, those at 14q32.2 lay out with any obvious nearby target. Instead, like those juxtaposing TLX3 (1 , 5) , they were scattered over 1 Mb distal (centromeric) of BCL11B, a zinc-finger transcription factor preferentially expressed in T cells (4 , 5) . The immediately centromeric gene, HERV-HD1/HSU88895, an endogenous retrovirus known to mediate ectopic gene expression in T cells (17) , lies just telomeric of the breakpoint cluster. Centromeric of the breakpoint cluster, the nearest annotated gene is VRK1, which regulates p53 by phosphorylation (18) . RT-PCR analysis showed that VRK1 and HSU88895 were expressed in both CCRF-CEM and PEER (data not shown) and in most hematopoietic and solid tumor cell lines examined (5) , whereas BCL11B was preferentially expressed in T-ALL cell lines (8 of 22) but rarely in other hematopoietic (1 of 6) or solid tumor (0 of 7) cell lines (Table 2) . Interestingly, BCL11B was expressed in HPB-ALL and CCRF-CEM but not in PEER. In addition, two alternative splicing products (variants 1 and 2, NM_138576/022898, respectively) were analyzed by RT-PCR (Fig. 2E ; Table 2 ). Variant 1 was only detectable in cell lines with t(5;14). Nine breakpoints at 3'-BCL11B have now been mapped, broadcast over circa 1 Mb (Fig. 1F) . The cytogenetic data imply that the putative regulatory region lies centromeric of this cluster, bounded by PEER at 92.2 Mb.

Screening of T-ALL Cell Lines for NK-like Homeobox Gene Expression.
NKX2–5, as well as TLX1 and TLX3 whose expression promotes T-ALL, belongs to the NK-like family of homeobox genes (6) , first identified in Drosophila (19) . NK-family members exhibit conservation of specific sequences within the homeodomain. In addition, most NK-homeobox genes, including NKX2–5, TLX3, and TLX1, contain so-called TN- and NK2-domains in their respective NH₂- and COOH-terminal regions (20) . Hitherto, 14 NK-like homologues have been described in Homo sapiens (Table 1) . To study the expression of other members of this group in T-ALL, a clue to ectopic activation, we screened 22 T-ALL cell lines by RT-PCR (Table 2) . In addition to NKX2–5, PEER, but not BE-13, expressed TLX1 mRNA (Fig. 2A) without any cytogenetic rearrangement of TLX1, whether analyzed conventionally or by FISH using flanking clones (data not shown). However, TLX1 protein was undetectable in PEER (Fig. 2D) . No additional T-ALL cell line expressed any of the 11 other NK-like homologue tested. Thus, TLX1 (ALL-SIL, K3P, PER-255, SUP-T4), TLX3 (HPB-ALL), and NKX2–5 (PEER, CCRF-CEM) were the only NK-like homeobox genes both expressed and translated in T-ALL cell lines (8) .

	DISCUSSION

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We have identified a novel variant t(5;14)(q35.1;q32.2) in pediatric T-ALL cells, whereby NKX2–5 is activated instead of TLX3, thereby adding NKX2–5 to the list of leukemogenic homeobox genes. Although mutations of NKX2–5, the human structural and functional homologue of the Drosophila tinman which specifies cardiac muscle progenitors in nascent mesoderm, cause atrial septal heart defects, expression has yet to be recorded in neoplastic tissue. NKX2–5 shares with TLX1 embryonal expression in spleen (12 , 21 , 22) , and both promote cell survival (22 , 23) . This may point to a similar genetical program controlled by NK-like homeobox genes, reactivation of which may promote development of T-cell leukemia, contrasting with NK genes involved in solid tumors, which are usually down-regulated.

Contrasting models may be invoked to explain activation of NKX2–5 or TLX3 in T-ALL by t(5;14). First, chromosome rearrangement may remove upstream negative regulators, as reported for TLX1 (24) . Or, their removal may target silencing of tissue-preferential regulators (25) . Alternately, (a) long-range tissue-specific distal-BCL11B regulatory element(s) enhance NKX2–5 promoter activity by chromosomal juxtaposition. The last model explains the consistent recurrence of t(5;14) in T-ALL and also permits analogy of 3'-BCL11B with IGH-enhancers, as implied by the data of Hansen-Hagge et al. (7) . Although the homologous BCL11A is a dominant oncogene (4) , the leukemogenic role of BCL11B, as evidenced by its nonexpression in PEER, remains unclear. Although neighboring genes, including HSU88895 and VRK1 as well as interspersed putative genes (UniGene Clusters), either strain the breakpoint data or fail to exhibit preferential expression in T cells (5) , it would be premature to abandon their candidacy in favor of BCL11B.

This report identifies pediatric T-ALL cell lines with a variant t(5;14) in which a novel homeodomain target, NKX2–5, is ectopically activated. Interestingly, the affected cell lines derive from female patients contrasting with the strong male preference hitherto observed in standard t(5;14) T-ALL (1 , 3) . Pediatric T-ALL samples will require testing for both NKX2–5 and TLX3 expression and/or modified FISH analysis to ascertain its clinical incidence, gender preference, and lineage associations. Preliminary data suggest that variant t(5;14) occurs more rarely than the standard translocation. Assessment of NKX2–5 as a potential new therapeutic target is currently underway in this lab. In addition to modeling a specific subtype of pediatric T-ALL, the cell lines described in this report should aid investigation of ectopic, NK-like homeodomain gene expression, and the nature of their putative activator(s) at 14q32.2, which appears to represent an emerging new pathological mechanism in T-cell leukemia.

	ACKNOWLEDGMENTS

 
We thank Olivier Bernard for critically reading this manuscript. We also thank him, Jonathan Flint, Hans Janssen, and Reiner Siebert for donating DNA clones.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Grant SP 02/01 from the German José Carreras Leukemia Fund.

² To whom requests for reprints should be addressed, at DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen), Department of Human and Animal Cell Cultures, Mascheroder Weg 1b, 38124 Braunschweig, Germany. Phone: 49 531 2616 167; Fax: 49 531 2616 150; E-mail: rml{at}dsmz.de

³ The abbreviations used are: FISH, fluorescence in situ hybridization; ALL, acute lymphoblastic leukemia; NK, natural killer; BAC, bacterial artificial chromosome; RT-PCR, reverse transcription-PCR; T-ALL, T-cell ALL; UBTF, upstream binding transcription factor.

⁴ Internet address: http://www.dsmz.de.

Received 5/ 9/03. Revised 6/16/03. Accepted 6/24/03.

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