Abstract
Loss of heterozygosity of the short arm of chromosome 12 is a frequent event in a wide range of haematological malignancies and solid tumours. In previous studies, the shortest commonly deleted region was delimited to a 750-kb interval, defined by the markers D12S89 and D12S358, in pre-B acute lymphoblastic leukaemia patients, suggesting the presence of a tumour suppressor locus. Here we report the construction of a transcriptional map that integrates the data obtained by genomic sequence analysis, EST database search, comparative analysis and exon amplification. We identified seven putative transcriptional units as well as six pseudogenes. Four of these candidate genes were already known: ETV6, encoding an ets-like transcription factor, LRP6, a member of the LDL receptor gene family, BCL-G, a recently identified pro-apoptotic gene and MKP-7, encoding a new member of the dual-specificity phosphatase family. The products encoded by the three new genes identified in this study, LOH1CR12, LOH2CR12 and LOH3CR12, have no clear homology to known proteins. The gene predictions were all confirmed by expression analysis using RT–PCR and Northern blot. This transcriptional map is a crucial step toward the identification of the tumour suppressor gene at 12p12.
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References
Berger R, Bernheim A, Le Coniat M et al. Abnormalities of the short arm of chromosome 12 in acute nonlymphocytic leukemia and dysmyelopoietic syndrome Cancer Genet Cytogenet 1986 19: 281–289
Raimondi SC, Williams DL, Callihan T, Peiper S, Rivera GK, Murphy SB . Nonrandom involvement of the 12p12 breakpoint in chromosome abnormalities of childhood acute lymphoblastic leukemia Blood 1986 68: 69–75
Chan LC, Kwong YL, Liu HW, Lee CP, Lie KW, Chan AY . Deletion 12p in de novo acute myeloid leukemia. An association with early progenitor cell Cancer Genet Cytogenet 1992 62: 47–49
Raimondi SC . Current status of cytogenetic research in childhood acute lymphoblastic leukemia Blood 1993 81: 2237–2251
Stegmaier K, Pendse S, Barker GF et al. Frequent loss of heterozygosity at the TEL gene locus in acute lymphoblastic leukemia of childhood Blood 1995 86: 38–44
Takeuchi S, Bartram CR, Miller CW et al. Acute lymphoblastic leukemia of childhood: identification of two distinct regions of deletion on the short arm of chromosome 12 in the region of TEL and KIP1 Blood 1996 87: 3368–3374
Baccichet A, Qualman SK, Sinnett D . Allelic loss in childhood acute lymphoblastic leukemia Leuk Res 1997 21: 817–823
Baccichet A, Sinnett D . Frequent deletion of chromosome 12p12.3 in children with acute lymphoblastic leukaemia Br J Haematol 1997 99: 107–114
Aissani B, Sinnett D . Fine physical and transcript mapping of a 1.8 Mb region spanning the locus for childhood acute lymphoblastic leukemia on chromosome 12p123 Gene 1999 240: 297–305
Baens M, Wlodarska I, Corveleyn A, Hoornaert I, Hagemeijer A, Marynen P . A physical, transcript, and deletion map of chromosome region 12p12.3 flanked by ETV6 and CDKN1B: hypermethylation of the LRP6 CpG island in two leukemia patients with hemizygous del(12p) Genomics 1999 56: 40–50
Aissani B, Bonan C, Baccichet A, Sinnett D . Childhood acute lymphoblastic leukemia: is there a tumor suppressor gene in chromosome 12p12.3? Leuk Lymphoma 1999 34: 231–239
Kibel AS, Freije D, Isaacs WB, Bova GS . Deletion mapping at 12p12-13 in metastatic prostate cancer Genes Chromosomes Cancer 1999 25: 270–276
Brown SD, Twells RC, Hey PJ et al. Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family Biochem Biophys Res Commun 1998 248: 879–888
Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC . An LDL-receptor-related protein mediates Wnt signalling in mice Nature 2000 407: 535–538
Tamai K, Semenov M, Kato Y et al. LDL-receptor-related proteins in Wnt signal transduction Nature 2000 407: 530–535
Wehrli M, Dougan ST, Caldwell K et al. Arrow encodes an LDL-receptor-related protein essential for Wingless signalling Nature 2000 407: 527–530
Golub TR, Barker GF, Lovett M, Gilliland DG . Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation Cell 1994 77: 307–316
Van Rompaey L, Dou W, Buijs A, Grosveld G . Tel, a frequent target of leukemic translocations, induces cellular aggregation and influences expression of extracellular matrix components Neoplasia 1999 1: 526–536
Fenrick R, Wang L, Nip J et al. TEL, a putative tumor suppressor, modulates cell growth and cell morphology of ras-transformed cells while repressing the transcription of stromelysin-1 Mol Cell Biol 2000 20: 5828–5839
Stegmaier K, Takeuchi S, Golub TR, Bohlander SK, Bartram CR, Koeffler HP . Mutational analysis of the candidate tumor suppressor genes TEL and KIP1 in childhood acute lymphoblastic leukemia Cancer Res 1996 56: 1413–1417
Thompson JD, Higgins DG, Gibson TJ . CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice Nucleic Acids Res 1994 22: 4673–4680
Baens M, Peeters P, Guo C, Aerssens J, Marynen P . Genomic organization of TEL: the human ETS-variant gene 6 Genome Res 1996 6: 404–413
Roest Crollius H, Jaillon O, Bernot A et al. Estimate of human gene number provided by genome-wide analysis using Tetraodon nigroviridis DNA sequence Nat Genet 2000 25: 235–238
Guo B, Godzik A, Reed JC . Bcl-G, a novel pro-apoptotic member of the Bcl-2 family J Biol Chem 2001 276: 2780–2785
Tanoue T, Yamamoto T, Maeda R, Nishida E . A Novel MAPK phosphatase MKP-7 acts preferentially on JNK/SAPK and p38 alpha and beta MAPKs J Biol Chem 2001 276: 26629–26639
Martell KJ, Seasholtz AF, Kwak SP, Clemens KK, Dixon JE . hVH-5: a protein tyrosine phosphatase abundant in brain that inactivates mitogen-activated protein kinase J Neurochem 1995 65: 1823–1833
Denu JM, Dixon JE . Protein tyrosine phosphatases: mechanisms of catalysis and regulation Curr Opin Chem Biol 1998 2: 633–641
Poirel H, Oury C, Carron C et al. The TEL gene products: nuclear phosphoproteins with DNA binding properties Oncogene 1997 14: 349–357
Wang LC, Kuo F, Fujiwara Y, Gilliland DG, Golub TR, Orkin SH . Yolk sac angiogenic defect and intra-embryonic apoptosis in mice lacking the Ets-related factor TEL EMBO J 1997 16: 4374–4383
Wang LC, Swat W, Fujiwara Y et al. The TEL/ETV6 gene is required specifically for hematopoiesis in the bone marrow Genes Dev 1998 12: 2392–2402
Lopez RG, Carron C, Oury C, Gardellin P, Bernard O, Ghysdael J . TEL is a sequence-specific transcriptional repressor J Biol Chem 1999 274: 30132–30138
Chakrabarti SR, Nucifora G . The leukemia-associated gene TEL encodes a transcription repressor which associates with SMRT and mSin3A Biochem Biophys Res Commun 1999 264: 871–877
Polakis P . Wnt signaling and cancer Genes Dev 2000 14: 1837–1851
Dahia PL . PTEN, a unique tumor suppressor gene Endocr Relat Cancer 2000 7: 115–129
Bonneau D, Longy M . Mutations of the human PTEN gene Hum Mutat 2000 16: 109–122
Debant A, Serra-Pages C, Seipel K et al. The multidomain protein Trio binds the LAR transmembrane tyrosine phosphatase, contains a protein kinase domain, and has separate rac- specific and rho-specific guanine nucleotide exchange factor domains Proc Natl Acad Sci USA 1996 93: 5466–5471
Seipel K, Medley QG, Kedersha NL et al. Trio amino-terminal guanine nucleotide exchange factor domain expression promotes actin cytoskeleton reorganization, cell migration and anchorage-independent cell growth J Cell Sci 1999 112: 1825–1834
Rapraeger AC . Molecular interactions of syndecans during development Semin Cell Dev Biol 2001 12: 107–116
Edwalds-Gilbert G, Veraldi KL, Milcarek C . Alternative poly(A) site selection in complex transcription units: means to an end? Nucleic Acids Res 1997 25: 2547–2561
Miyamoto S, Chiorini JA, Urcelay E, Safer B . Regulation of gene expression for translation initiation factor eIF-2 alpha: importance of the 3′ untranslated region Biochem J 1996 315: 791–798
Acknowledgements
We thank Zeina Saikali for critical reading of this manuscript. This work was supported by the Canadian Institutes of Health Research (CIHR). Daniel Sinnett is a scholar of the Fonds de la Recherche en Santé du Québec (FRSQ). Alexandre Montpetit and Gino Boily have received studentships from the CIHR and from the FRSQ, respectively.
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Montpetit, A., Boily, G. & Sinnett, D. A detailed transcriptional map of the chromosome 12p12 tumour suppressor locus. Eur J Hum Genet 10, 62–71 (2002). https://doi.org/10.1038/sj.ejhg.5200766
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DOI: https://doi.org/10.1038/sj.ejhg.5200766
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