Identification of the TCL1/MTCP1-Like 1 (TML1) Gene from the Region Next to the TCL1 Locus1

[CANCER RESEARCH 59, 2313–2317, May 15, 1999] Advances in Brief

Identification of the TCL1/MTCP1-like 1 (TML1) Gene from the Region Next to the TCL1 Locus1

Jun Sugimoto, Toyomasa Hatakeyama, Maria Grazia Narducci, Giandomenico Russo, and Masaharu Isobe2 Department of Materials and Biosystem Engineering, Faculty of Engineering, Toyama University, Toyama City, 930-8555 Japan [J. S., T. H., M. I.]; and IDI-IRCCS, Research Laboratories, 00167 Rome, Italy [M. G. N., G. R.]

Abstract malignant clonal expansion of T cells of patients with AT. We and others have cloned numerous breakpoints at 14q32.1 involved in The region on chromosome 14q32.1 is frequently involved in chromo- T-cell neoplasms (7–11). By placing these breakpoints on the map of somal translocations and inversions with one of the T-cell receptor loci in the region, we found that the breakpoints involve a chromosomal human T-cell leukemias and lymphomas. The breakpoints of the different ϳ rearrangements segregate into two clusters: inversion on the centromeric segment of 400 kb and cluster in two regions (12). The centromeric side and simple balanced translocations on the telomeric side. If the target region is mainly involved in inversions, whereas the telomeric region gene activated by these different types of chromosomal rearrangements is is involved in simple translocations. These two regions enclose a the same, the gene must reside between the two clusters of breakpoints in segment of ϳ160 kb. We postulated that, if the oncogene activated by a region of ϳ160 kb. By screening of a placenta cDNA library using these different rearrangements is the same, it must reside between genomic probes derived from the vicinity of TCL1 locus, we have identi- these two clusters of breakpoints. Within this region, we have previ- fied a gene coding for a 1.7-kb transcript that is expressed in leukemic ously identified a gene named TCL1 (13) that is activated and dereg- cells carrying a t(14;14)(q11;q32) chromosome translocation. The cognate ulated by the chromosomal translocations and inversions. The se- cDNA sequence reveals an open reading frame of 384 nucleotides encod- ϳ TCL1 quence of the TCL1 gene revealed that it is highly homologous to that ing a Mr 15,000 protein with 30% of homology with both p14 and p13MTCP1 oncoproteins. The genomic organization of the TML1 locus was of the MTCP1 (B1) gene, which has been isolated from the breakpoint characterized, with three exons located 15 kb from and tail-to-tail in of t(X;14)(q28;q11) translocation, found in rare cases of AT (14). The relation to TCL1 locus. Because of its location and sequence similarity with MTCP1 (B1) gene at Xq28 was also activated by juxtaposing with TCL1 and MTCP1 oncoproteins, this gene, named TML1 (TCL1/MTCP1- TCRA/D region at 14q11. The TCL1 and MTCP1 genes encode two like 1) is a candidate gene that is potentially involved in leukemogenesis. homologous proteins, p14TCL1 and p13MTCP1, which share no simi- Introduction larities with any other known proteins. Both TCL1 and MTCP1 transgenic mice developed T-cell leukemia at an old age (15, 16). In Nonrandom chromosomal translocations are characteristic of most contrast to AT patients, who develop evident clonal expansion of T human hematopoietic malignancies (1). In B and T cells, chromo- cells by the age of 20 years, the occasional clonal expansion of T cells somal translocations and inversions often occur as a consequence of in TCL1 transgenic mice was not observed until at least 12 months mistakes during the normal process of recombination of the genes for after birth. Furthermore, the size of region affected by translocations immunoglobulins or TCRs.3 These rearrangements juxtapose en- with TCR loci (160 kb) is far larger than that of TCL1 locus (Ͻ10 kb). hancer elements of the immunoglobulin or TCR genes to oncogenes, These results suggested that there might be an additional gene that the expression of which is then deregulated (2). In T-cell tumors, the contributes to the development of clonal expansion of T cells at a TCR genes located on chromosomes 14q11 (TCRA/D; Refs. 3 and 4), younger age. Thus, we screened human cDNA libraries to look for 7q35 (TCRB; Ref. 5), and 7p15 (TCRG; Ref. 6) occasionally cause genes in this affected region. By using a cosmid clone derived from translocations or inversions as a consequence of the faulty joining of this region as a probe, we were able to identify a novel gene that has genes during the physiological process, leading to VDJ recombina- significant homology with the TCL1 and MTCP1 genes and is ex- tion. Chromosome region 14q32.1 is commonly involved in chromo- pressed in T-cell leukemias carrying the translocation t(14;14)(q11; somal rearrangements with TCR loci in several T-cell neoplasms. q32.1). Chromosome abnormalities, such as the inversion inv(14)(q11q32) and translocations t(14;14)(q11;q32) and t(7;14)(q35;q32), are fre- Materials and Methods quently observed in: T-cell prolymphocytic leukemia, a rare form of mature T-cell proliferations; chronic and acute T-cell leukemias aris- Cell Lines and Lymphocytes. The majority of the cell lines used in this ing in patients with the immunodeficiency syndrome AT; and non- study were obtained from American Type Culture Collection (Manassas, VA). The SupT11 cell line was derived from patient NL (17). PBLs were isolated Received 3/2/99; accepted 3/30/99. from whole blood by centrifugation on a Ficoll-Hypaque gradient, followed by The costs of publication of this article were defrayed in part by the payment of page a 1-h adherence to Petri dishes to remove the monocytes. Stimulation with charges. This article must therefore be hereby marked advertisement in accordance with PHA at a final concentration of 0.1% was carried out for 3 days. 18 U.S.C. Section 1734 solely to indicate this fact. Isolation of Cosmid Clones Surrounding the TCL1 Locus. A YAC 1 This work was supported in part by Grant-in-Aid from the Ministry of Education Science and Culture Japan (to M. I.), Associazione Italiana Ricerca sul Cancro and clone, 964D10, was identified from the CEPH mega YAC library (Centre Ministero della Sanita´Italiana (G. R.) and by Grant No. RG-350/96 from Human Frontier d’E´ tude du Polymorphisme Humain, France) by screening with PCR using Science Program (to M. I. and G. R.). primers corresponding to TCL1 locus. DNA from YAC 964D10 was partially 2 To whom requests for reprints should be addressed, at Laboratory of Molecular and Cellular Biology, Department of Materials and Biosystem Engineering, Faculty of Engi- digested with the Sau3AI restriction enzyme and fractionated into 40–50-kb neering, Toyama University, 3190 Gofuku, Toyama City, 930-8555 Japan. E-mail: fragments by sucrose gradient ultracentrifugation. The resulting DNA frag- [email protected]. ments were ligated into pMFG2 cosmid vector, which was constructed by 3 The abbreviations used are: TCR, T-cell receptor; AT, ataxia-telangiectasia; PBL, introduction of bacteriophage T3 and T7 promoters on both sides of a BamHI peripheral blood lymphocyte; PHA, phytohemagglutinin; YAC, yeast artificial chromosome; RACE, rapid amplification of cDNA ends; RT-PCR, reverse transcription-PCR; site and two NotI sites on both sides of a BamHI site in a pHSG274 vector. The ORF, open reading frame. ligated DNA was transformed into Escherichia coli HB101 after in vitro 2313

Fig. 1. Genomic and cDNA organization of the TML1 and TCL1 genes. A, restriction map of the TML1 and TCL1 loci on chromosome 14q32.1 (11). Vertical arrows, cloned breakpoints in the literature (7, 9, 17, 23, 24). Horizontal arrows with open arrowheads, orientation of TCR region with respect to breakpoints. Horizontal bars, positions of P1 clones 7-4 and 20-7 (11) and cosmid clone cos231. b, close-up of restriction map corresponding to both loci. c, organization of three exons of the TML1 gene and four exons of the TCL1 gene are indicated. Arrows, direction of the transcripts. ᮀ,5Ј and 3Ј untranslated regions; ■, coding sequences. packaging. The colony hybridization was performed by using [32P]dCTP- 23-mer sense primer (AP2) and TML1-primer 137AS (5Ј-CGAGGGATT- labeled human CotI DNA as a probe to obtain human cosmid clones. GAACCGCACGAC-3Ј). The condition for both PCRs was 95°C for 30 s, Direct cDNA Library Screening. The human placenta cDNA library 55°C for 30 s, and 68°C for 4 min for 20–30 cycles. The amplified products constructed in ␭gt10 vector was purchased from Clontech (Palo Alto, CA). were subcloned into a pNoTA/T7 vector using Prime PCR Cloner kit (5 Cosmid DNA that was used as a probe was prepared by a standard alkaline prime-3 prime, Inc. Boulder, CO), and sequenced by dideoxynucleotide chain- lysis method, purified by ethidium bromide-CsCl centrifugation to eliminate termination method. Both strands of the cDNA clones were sequenced. any E. coli DNA contamination, and then labeled by nick translation using RT-PCR. First-strand cDNA synthesis was performed using 1 ␮g of total [32P]dCTP. The labeled cosmid DNA was precipitated with 20 ␮g of human RNA with Superscript II reverse transcriptase (Life Technologies, Inc, Gaith- CotI DNA (Roche Biochemicals, Basel, Switzerland) and 10 ␮g of pMFG2 ersburg, MD) and oligo(dT) as a primer; 10% of the reaction mixture was vector in ethanol and dissolved in 10 ␮lof5ϫ SSC, followed by denaturation subsequently used for each single PCR amplification. Amplification of each in boiling water for 5 min and incubation at 65°C for 1 h. Hybridization of cDNA from human cell lines and human normal tissues was carried out under preannealed cosmid probe onto the cDNA library was carried out in a solution the following conditions: denaturing for 1 min at 95°C, annealing for 1 min at of 50% formamide, 4ϫ SSC, 5ϫ Denhardt’s solution, and 125 ␮g/ml dena- 55°C, and elongation for 2 min at 72°C for 30 cycles. The TML1-specific tured salmon sperm DNA at 37°C overnight. Filters were washed twice at primers TML1 14S (5Ј-CCCGGTTGCAGACTTGCCATG-3Ј) and TML1 55°C for 10 min in 2ϫ SSC and once at 55°C for 10 min in 1ϫ SSC, subjected 247AS (5Ј-CTGGCCGGAGGAGAGTAGC-3Ј) and the TCL1-specific prim- to a final rinse with 2ϫ SSC at room temperature, and then exposed to Kodak ers TCL1 12S (5Ј-CTGGCTCTTGCTTCTTAGGCGG-3Ј) and TCL1 386AS X-ray film for 48 h. (5Ј-GTGCTGCCAAGACCATACATCAGT-3Ј) were used for the amplifica- -5؅ RACE. The 5Ј RACE was performed by using the Marathon cDNA tion. Amplification with the G3PDH-specific primers G3PDH-5Ј (5Ј-ACCA amplification kit (Clontech), per the manufacturer’s recommendations. First- CAGTCCATGCCATCAC-3Ј) and G3PDH-3Ј (5Ј-TCCACCACCCTGTT- strand synthesis of 1 ␮g of poly(A) RNA from human placenta or a Burkitt’s GCTGTA-3Ј) was performed as a control. The resulting products were lymphoma cell line (Daudi) was performed using a modified lock-docking detected by staining with ethidium bromide after fractionation of a 6% poly- oligo(dT) primer that consists of two degenerate nucleotide positions at the 3Ј acrylamide gel or a 1.5% agarose gel. The specificity of each amplified end. After second-strand synthesis, the cDNA pool was blunt end ligated to the product was confirmed by hybridization with digoxigenin-labeled gene- cDNA adaptors. The first PCR was performed with 27-mer sense primer (AP1) specific oligonucleotide. specific for the adaptor and TML1-primer 369AS (5Ј-CTGGCCGGAG- In Vitro Translation. A plasmid, pTML1 ORF, containing full-length GAGAGTAGC-3Ј). The second round of PCR was performed with a nested TML1 cDNA was linearized by digestion with XhoI and transcribed and 2314

Fig. 2. The cDNA sequence of TML1. The initiation codon ATG shown in a box, and the polyadenylation signal is under- lined. Arrows, boundaries of each exon. The sequence accession number of DDBJ for the TML1 cDNA genomic sequences corresponding to each exon are ABO18563, ABO25272, ABO25273, and ABO25274, respectively.

translated in vitro using the ECL in vitro translation system (Amersham, codon at position 32 in a stretch of sequence GCCATGG that Buckinghamshire, England). matches Kozack consensus sequence [(A/G)NNATG(A/G)] and a Northern Blot Analysis. Poly(A) RNA was isolated by using PolyAT- stop codon at position 416 (Fig. 2). This ORF potentially encodes ␮ tract system 1000 kit (Promega, Madison, WI). Ten g of poly(A) RNA for a protein of 128 amino acids, with a predicted molecular mass were electrophoresed on a 1% agarose gel. RNA was then transferred to of 15 kDa. Frame 2 contains an ORF with a starting ATG codon at nitrocellulose and hybridized with a [32P]dCTP-labeled pTML1 cDNA position 1089 in a stretch of sequence TTCATGT and a stop codon probe overnight at 37°C in 50% formamide, 5ϫ SSC, 5ϫ Denhardt’s solution, 0.1% SDS, and 20 ␮g/ml denatured salmon sperm DNA. This was at position 1520, to give a putative protein with a mass of 15.8 followed by one wash in 2ϫ SSC-0.1% SDS at room temperature for 10 kDa. However, the sequence surrounding ATG in frame 2 does not min, two washes in 0.1ϫ SSC-0.1% SDS at room temperature for 10 min, match Kozack consensus and the ORF in frame 2 only presents in and one wash in 1ϫ SSC-0.1% SDS at 50°C for 10 min. The filter was the last exon. Thus, it is less likely that the ORF in frame 2 is wrapped and subjected to autoradiography using Kodak X-ray films (East- translated. To confirm the presence of an ORF and its ability to man Kodak, Rochester, NY). encode a protein, the cDNA containing either a frame 1 or frame 2 sequence was subcloned, and an in vitro translation was per- Results formed. The specific product of a Mr 15,000 protein was only Cloning and Sequence Analysis of the TML1 Gene. To identify detected in transcript coding for frame 1 (data not shown). Inter- transcribed sequences between the two clusters of breakpoints as estingly, the homology search of the deduced amino acid sequence illustrated in Fig. 1, we first isolated cosmid clones from YAC clone from frame 1 revealed a significant homology with p14TCL1 and (964B10) encompassing TCL1 locus. We obtained total of 250 human p13MTCP1, as shown in Fig. 3. The sequence has identities of 29 cosmid clones from YAC 964D10. We then used them for the direct and 32% and similarities of 36 and 36% with human p14TCL1 and screening of several human cDNA libraries. When we screened a p13MTCP1, respectively. Thus, we designated this gene and its placenta cDNA library with one of the cosmid clones, cos231 con- deduced product as TCL1/MTCP1 like 1 (TML1) gene and taining TCL1 locus as a probe, one positive clone was obtained and p15TML1 protein. designated pPL1. Sequence analysis of cDNA clone pPL1 revealed Genomic Structure of the TML1 Gene. To study the genomic the presence of an ORF lacking translation initiation codon. Thus, we structure of TML1 gene, we isolated and sequenced subclones corre- further proceeded to 5Ј RACE experiments using mRNAs from pla- sponding to the entire TML1 gene from P1 clones (P1 7-4 and P1 centa to obtain cDNA clone corresponding to the 5Ј region and 20-7). The map and structure of the TML1 gene are shown together yielded many overlapping cDNA clones of 0.3 kb. One of the longest with those of the TCL1 gene in Fig. 1. The TML1 locus maps 15 kb cDNA clones was named pMPLB4. centromeric to the TCL1 locus with a tail-to-tail orientation. Thus, the All cDNA clones were entirely sequenced, and the complete TML1 and TCL1 genes use independent promoter regions. The TML1 nucleotide sequences of pPL1, and pMPLB4 produced a combined gene is composed of three small exons with a 3Ј untranslated region sequence of 1753 bp, followed by 30-bp poly(A) tail, as shown in of 1338 nucleotides. Donor and acceptor signal sequences are in good Fig. 2. Sequence analysis showed the presence of two long ORFs. agreement with the consensus signal sequences, except for the exon- Frame 1 contains an ORF of 384 nucleotides with a starting ATG intron boundary of exon 2 (AG/gc instead of AG/gt) (18). 2315

Fig. 3. Comparison of deduced amino acid sequence of the TML1 gene with human p13 MTCP1 (14), murine p13 MTCP1 (25), human TCL1 (19), and murine TCL1 (15). Boxed regions, homologies within p13 MTCP1 and TCL1 from human and mouse. *, complete identity for all family members; •, similarity for all family members.

Expression of the TML1 Gene in Tumors and Normal Human Discussion Tissues. To determine whether the isolated gene is deregulated in cells with the t(14;14)(q11;q32) translocation, we carried out a North- The TML1 gene is located in a chromosomal region banded by two ern blot analysis comparing the amount of TML1 transcript present in clusters of breakpoints. In its strategic position, between the two resting PBLs, PHA-activated PBLs, and SupT11 cells [a cell line clusters of breakpoints, the TML1 gene becomes juxtaposed to established from a patient with acute T-lymphocytic leukemia with a TCR-C␣ regulatory elements in both types of rearrangements involv- t(14;14) chromosomal translocation; Fig. 4a]. The cDNA clone pPL1 ing 14q32.1. The TML1 gene can be activated by the control elements identified an ϳ1.7-kb transcript. We detected similar levels of expres- of the TCR gene, where they are positioned 5Ј to the TML1 gene, as sion in SupT11 cells and PHA-stimulated PBLs, whereas a very weak in inversions, or 3Ј to TML1, as in translocations. A similar situation signal was detected from resting PBLs. To further investigate the has been observed in the TCL1 gene because of its proximity to the expression profile of TML1 gene, we performed sensitive RT-PCR TML1 gene (19). The expression of the TML1 gene in leukemic T cells assays of TML1 and compared the results with those of the TCL1 and with the t(14;14) translocation but not in leukemic T-cell lines with G3PDH genes (Fig. 4b). No expression was detectable in several other types of chromosomal rearrangements suggested that this gene other tumor-derived T-cell lines lacking the translocation involved in becomes deregulated as a consequence of its juxtaposition to the TML1 gene, such as MOLT-4, Jurkat, and SupT1 cells. Of interest is TCRA/D locus. the fact that SupT1 cells carry an inverted chromosome 14, The sequence analysis of the deduced protein of the TML1 gene inv(14)(q11;q32), in which the TCR-␣ locus is not juxtaposed to revealed that p15TML belongs to the third member of TCL1/ TML1 but is positioned in front of the variable segment of immuno- MTCP1 family. The results of crystal structure analysis indicated globulin heavy chain gene at 14q32.3. Thus, an inversion of chromo- that p14TCL1 and p13MTCP1 consist of an eight-stranded antiparal- some 14 that does not involve the TML1 locus is unable to deregulate lel ␤ barrels with novel topologies (20, 21). Because the sequences the TML1 gene. The expression profiles of the TML1 and TCL1 genes in the regions that formed ␤ strands in p14TCL1 and p13MTCP1 are were quite similar. The concomitant expressions of the TML1 and also well conserved in p15TML1, this protein probably forms struc- TCL1 genes were observed in PHA-stimulated PBLs, Burkitt’s lym- tures that are similar to those of the other two proteins. Moreover, phomas, and a T-cell leukemia carrying t(14;14)(q11;q32.1) translo- it has been reported that purified recombinant p14TCL1 forms cation, whereas expression of neither TML1 nor TCL1 was observed dimers in solution (22). Although further studies are required, it is in RNA isolated from a variety of normal human tissues, including possible that p15TCL1 also forms homodimers with itself or het- kidney, muscle, liver, lung, brain, heart, small intestine, and colon. erodimers with p14TCL1 in tumor cells coexpressing TML1 and The solo expression of the TML1 gene was only detected in placenta TCL1 gene such as endemic Burkitt’s or T-cell tumors with and testis within the normal tissues examined. 14q32.1 involvement. To date, no information is available to imply the molecular function of TCL1/MTCP1 family. The amino acid sequence similarities among p15TML1, p14TCL1, and p13MTCP1 suggest that their function may be analogous, and they are most probably involved in the control of lymphoid cell proliferation and/or survival. Except for the expression of TML1 in placenta and testis, the expression pattern of the TML1 gene is well correlated with that of TCL1. This suggests that concomitant expression of both genes may play an important role in the clonal expansion of T cells and leukemogenesis. Thus, it would be interesting to know whether the TML1 gene is capable of forming tumors by itself in transgenic mice or accelerating the clonal expansion and/or tumor formation in combi- nation of double transgenic mice harboring both the TML1 and TCL1 genes, as in clonal T cells and leukemic T-cells with t(14;14) trans- Fig. 4. Expression of the TML1 gene. a, Northern blot hybridization with a pPL1 probe. locations in AT patients. Each lane contained 10 ␮g of poly(A) RNA from the following cells and a cell line: Lane 1, PBLs stimulated with PHA; Lane 2, unstimulated PBLs; Lane 3, SupT11. b, RT-PCR In conclusion, the TML1 gene is a strong candidate for an oncogene analysis of the TML1 and TCL1 genes. Lanes 1–19, Daudi, Raji, SupT11, SupT1, Jurkat, because it is deregulated by translocation with TCR locus, and the MOLT4, K562, HD-70, stomach, kidney, muscle, liver, lung, placenta, brain, heart, testis, small intestine, and colon, respectively. Top, TML1 primers; middle, TCL1 primers; deduced protein of TML1 gene has a striking homology with the bottom, control G3PDH primers. p14TCL1 and p13MTCP1 oncoproteins. 2316

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Jun Sugimoto, Toyomasa Hatakeyama, Maria Grazia Narducci, et al.

Cancer Res 1999;59:2313-2317.

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