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Analysis of copy number variations of BS69 in multiple types of hematological malignancies

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Abstract

BS69 was originally identified as an adenovirus E1A-binding protein and was found to be involved in multiple cellular events. A recent array-based study implicated the presence of copy number variations (CNVs) of BS69 in the genomes of acute myelogenous leukemia. CNVs are present in the general population at varying degrees and have been found to associate with various types of diseases including hematological malignancies. However, most of the current studies focused on the genome-wide screening of CNVs, and the functional impact of such regions needs to be extensively investigated in large amount of clinical samples. Thus, in our study, we collected 617 bone marrow samples from multi-types of hematological malignancies as well as healthy controls. We found significant association between the CNVs of BS69 and these hematological malignancies including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma (MM), and myelodysplastic syndrome (MDS). We also examined the expression of BS69 mRNA in the samples with one or two copies of DNA, and observed a weak yet positive correlation between the relative expression level and gene dosage. In general, the CNVs of BS69 have the potential to serve as a diagnostic indicator, alone or in combination with other markers, for hematological malignancies.

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References

  1. Hateboer G, Gennissen A, Ramos YF, Kerkhoven RM, Sonntag-Buck V, Stunnenberg HG, Bernards R (1995) BS69, a novel adenovirus E1A-associated protein that inhibits E1A transactivation. EMBO J 14:3159–3169

    CAS  PubMed  Google Scholar 

  2. Ikeda O, Miyasaka Y, Yoshida R, Mizushima A, Oritani K, Sekine Y, Kuroda M, Yasui T, Fujimuro M, Muromoto R, Nanbo A, Matsuda T: BS69 cooperates with TRAF3 in the regulation of Epstein-Barr virus-derived LMP1/CTAR1-induced NF-kappaB activation. FEBS Lett

  3. Ikeda O, Sekine Y, Mizushima A, Oritani K, Yasui T, Fujimuro M, Muromoto R, Nanbo A, Matsuda T (2009) BS69 negatively regulates the canonical NF-kappaB activation induced by Epstein-Barr virus-derived LMP1. FEBS Lett 583:1567–1574

    Article  CAS  PubMed  Google Scholar 

  4. Wan J, Zhang W, Wu L, Bai T, Zhang M, Lo KW, Chui YL, Cui Y, Tao Q, Yamamoto M, Akira S, Wu Z (2006) BS69, a specific adaptor in the latent membrane protein 1-mediated c-Jun N-terminal kinase pathway. Mol Cell Biol 26:448–456

    Article  CAS  PubMed  Google Scholar 

  5. Masselink H, Bernards R (2000) The adenovirus E1A binding protein BS69 is a corepressor of transcription through recruitment of N-CoR. Oncogene 19:1538–1546

    Article  CAS  PubMed  Google Scholar 

  6. Ekblad CM, Chavali GB, Basu BP, Freund SM, Veprintsev D, Hughes-Davies L, Kouzarides T, Doherty AJ, Itzhaki LS (2005) Binding of EMSY to HP1beta: implications for recruitment of HP1beta and BS69. EMBO Rep 6:675–680

    Article  CAS  PubMed  Google Scholar 

  7. Hughes-Davies L, Huntsman D, Ruas M, Fuks F, Bye J, Chin SF, Milner J, Brown LA, Hsu F, Gilks B, Nielsen T, Schulzer M, Chia S, Ragaz J, Cahn A, Linger L, Ozdag H, Cattaneo E, Jordanova ES, Schuuring E, Yu DS, Venkitaraman A, Ponder B, Doherty A, Aparicio S, Bentley D, Theillet C, Ponting CP, Caldas C, Kouzarides T (2003) EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 115:523–535

    Article  CAS  PubMed  Google Scholar 

  8. Ladendorff NE, Wu S, Lipsick JS (2001) BS69, an adenovirus E1A-associated protein, inhibits the transcriptional activity of c-Myb. Oncogene 20:125–132

    Article  CAS  PubMed  Google Scholar 

  9. Masselink H, Vastenhouw N, Bernards R (2001) B-myb rescues ras-induced premature senescence, which requires its transactivation domain. Cancer Lett 171:87–101

    Article  CAS  PubMed  Google Scholar 

  10. Velasco G, Grkovic S, Ansieau S (2006) New insights into BS69 functions. J Biol Chem 281:16546–16550

    Article  CAS  PubMed  Google Scholar 

  11. Wei G, Schaffner AE, Baker KM, Mansky KC, Ostrowski MC (2003) Ets-2 interacts with co-repressor BS69 to repress target gene expression. Anticancer Res 23:2173–2178

    CAS  PubMed  Google Scholar 

  12. Zhang W, Chan HM, Gao Y, Poon R, Wu Z (2007) BS69 is involved in cellular senescence through the p53-p21Cip1 pathway. EMBO Rep 8:952–958

    Article  CAS  PubMed  Google Scholar 

  13. Yu B, Shao Y, Zhang C, Chen Y, Zhong Q, Zhang J, Yang H, Zhang W, Wan J (2009) BS69 undergoes SUMO modification and plays an inhibitory role in muscle and neuronal differentiation. Exp Cell Res 315:3543–3553

    Article  CAS  PubMed  Google Scholar 

  14. Ulger C, Toruner GA, Alkan M, Mohammed M, Damani S, Kang J, Galante A, Aviv H, Soteropoulos P, Tolias PP, Schwalb MN, Dermody JJ (2003) Comprehensive genome-wide comparison of DNA and RNA level scan using microarray technology for identification of candidate cancer-related genes in the HL-60 cell line. Cancer Genet Cytogenet 147:28–35

    Article  CAS  PubMed  Google Scholar 

  15. Walter MJ, Payton JE, Ries RE, Shannon WD, Deshmukh H, Zhao Y, Baty J, Heath S, Westervelt P, Watson MA, Tomasson MH, Nagarajan R, O'Gara BP, Bloomfield CD, Mrozek K, Selzer RR, Richmond TA, Kitzman J, Geoghegan J, Eis PS, Maupin R, Fulton RS, McLellan M, Wilson RK, Mardis ER, Link DC, Graubert TA, DiPersio JF, Ley TJ (2009) Acquired copy number alterations in adult acute myeloid leukemia genomes. Proc Natl Acad Sci USA 106:12950–12955

    Article  CAS  PubMed  Google Scholar 

  16. Conrad DF, Andrews TD, Carter NP, Hurles ME, Pritchard JK (2006) A high-resolution survey of deletion polymorphism in the human genome. Nat Genet 38:75–81

    Article  CAS  PubMed  Google Scholar 

  17. Hinds DA, Kloek AP, Jen M, Chen X, Frazer KA (2006) Common deletions and SNPs are in linkage disequilibrium in the human genome. Nat Genet 38:82–85

    Article  CAS  PubMed  Google Scholar 

  18. Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y, Scherer SW, Lee C (2004) Detection of large-scale variation in the human genome. Nat Genet 36:949–951

    Article  CAS  PubMed  Google Scholar 

  19. Kidd JM, Cooper GM, Donahue WF, Hayden HS, Sampas N, Graves T, Hansen N, Teague B, Alkan C, Antonacci F, Haugen E, Zerr T, Yamada NA, Tsang P, Newman TL, Tuzun E, Cheng Z, Ebling HM, Tusneem N, David R, Gillett W, Phelps KA, Weaver M, Saranga D, Brand A, Tao W, Gustafson E, McKernan K, Chen L, Malig M, Smith JD, Korn JM, McCarroll SA, Altshuler DA, Peiffer DA, Dorschner M, Stamatoyannopoulos J, Schwartz D, Nickerson DA, Mullikin JC, Wilson RK, Bruhn L, Olson MV, Kaul R, Smith DR, Eichler EE (2008) Mapping and sequencing of structural variation from eight human genomes. Nature 453:56–64

    Article  CAS  PubMed  Google Scholar 

  20. Korbel JO, Urban AE, Affourtit JP, Godwin B, Grubert F, Simons JF, Kim PM, Palejev D, Carriero NJ, Du L, Taillon BE, Chen Z, Tanzer A, Saunders AC, Chi J, Yang F, Carter NP, Hurles ME, Weissman SM, Harkins TT, Gerstein MB, Egholm M, Snyder M (2007) Paired-end mapping reveals extensive structural variation in the human genome. Science 318:420–426

    Article  CAS  PubMed  Google Scholar 

  21. McCarroll SA, Hadnott TN, Perry GH, Sabeti PC, Zody MC, Barrett JC, Dallaire S, Gabriel SB, Lee C, Daly MJ, Altshuler DM (2006) Common deletion polymorphisms in the human genome. Nat Genet 38:86–92

    Article  CAS  PubMed  Google Scholar 

  22. Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, Gonzalez JR, Gratacos M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME (2006) Global variation in copy number in the human genome. Nature 444:444–454

    Article  CAS  PubMed  Google Scholar 

  23. Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P, Maner S, Massa H, Walker M, Chi M, Navin N, Lucito R, Healy J, Hicks J, Ye K, Reiner A, Gilliam TC, Trask B, Patterson N, Zetterberg A, Wigler M (2004) Large-scale copy number polymorphism in the human genome. Science 305:525–528

    Article  CAS  PubMed  Google Scholar 

  24. Tuzun E, Sharp AJ, Bailey JA, Kaul R, Morrison VA, Pertz LM, Haugen E, Hayden H, Albertson D, Pinkel D, Olson MV, Eichler EE (2005) Fine-scale structural variation of the human genome. Nat Genet 37:727–732

    Article  CAS  PubMed  Google Scholar 

  25. Korbel JO, Urban AE, Grubert F, Du J, Royce TE, Starr P, Zhong G, Emanuel BS, Weissman SM, Snyder M, Gerstein MB (2007) Systematic prediction and validation of breakpoints associated with copy-number variants in the human genome. Proc Natl Acad Sci USA 104:10110–10115

    Article  CAS  PubMed  Google Scholar 

  26. Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, Catano G, Nibbs RJ, Freedman BI, Quinones MP, Bamshad MJ, Murthy KK, Rovin BH, Bradley W, Clark RA, Anderson SA (2005) O'Connell R J, Agan BK, Ahuja SS, Bologna R, Sen L, Dolan MJ, Ahuja SK: The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307:1434–1440

    Article  CAS  PubMed  Google Scholar 

  27. McKinney C, Merriman ME, Chapman PT, Gow PJ, Harrison AA, Highton J, Jones PB, McLean L, O'Donnell JL, Pokorny V, Spellerberg M, Stamp LK, Willis J, Steer S, Merriman TR (2008) Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis. Ann Rheum Dis 67:409–413

    Article  CAS  PubMed  Google Scholar 

  28. Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerriere A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 38:24–26

    Article  CAS  PubMed  Google Scholar 

  29. Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) Alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302:841

    Article  CAS  PubMed  Google Scholar 

  30. Andrews J, Kennette W, Pilon J, Hodgson A, Tuck AB, Chambers AF, Rodenhiser DI Multi-platform whole-genome microarray analyses refine the epigenetic signature of breast cancer metastasis with gene expression and copy number. PLoS One 5:e8665

  31. Diskin SJ, Hou C, Glessner JT, Attiyeh EF, Laudenslager M, Bosse K, Cole K, Mosse YP, Wood A, Lynch JE, Pecor K, Diamond M, Winter C, Wang K, Kim C, Geiger EA, McGrady PW, Blakemore AI, London WB, Shaikh TH, Bradfield J, Grant SF, Li H, Devoto M, Rappaport ER, Hakonarson H, Maris JM (2009) Copy number variation at 1q21.1 associated with neuroblastoma. Nature 459:987–991

    Article  CAS  PubMed  Google Scholar 

  32. Liu W, Sun J, Li G, Zhu Y, Zhang S, Kim ST, Sun J, Wiklund F, Wiley K, Isaacs SD, Stattin P, Xu J, Duggan D, Carpten JD, Isaacs WB, Gronberg H, Zheng SL, Chang BL (2009) Association of a germ-line copy number variation at 2p24.3 and risk for aggressive prostate cancer. Cancer Res 69:2176–2179

    Article  CAS  PubMed  Google Scholar 

  33. Grubor V, Krasnitz A, Troge JE, Meth JL, Lakshmi B, Kendall JT, Yamrom B, Alex G, Pai D, Navin N, Hufnagel LA, Lee YH, Cook K, Allen SL, Rai KR, Damle RN, Calissano C, Chiorazzi N, Wigler M, Esposito D (2009) Novel genomic alterations and clonal evolution in chronic lymphocytic leukemia revealed by representational oligonucleotide microarray analysis (ROMA). Blood 113:1294–1303

    Article  CAS  PubMed  Google Scholar 

  34. Gunnarsson R, Staaf J, Jansson M, Ottesen AM, Goransson H, Liljedahl U, Ralfkiaer U, Mansouri M, Buhl AM, Smedby KE, Hjalgrim H, Syvanen AC, Borg A, Isaksson A, Jurlander J, Juliusson G, Rosenquist R (2008) Screening for copy-number alterations and loss of heterozygosity in chronic lymphocytic leukemia–a comparative study of four differently designed, high resolution microarray platforms. Genes Chromosomes Cancer 47:697–711

    Article  CAS  PubMed  Google Scholar 

  35. Schafer M, Schwender H, Merk S, Haferlach C, Ickstadt K, Dugas M (2009) Integrated analysis of copy number alterations and gene expression: a bivariate assessment of equally directed abnormalities. Bioinformatics 25:3228–3235

    Article  PubMed  Google Scholar 

  36. Strefford JC, van Delft FW, Robinson HM, Worley H, Yiannikouris O, Selzer R, Richmond T, Hann I, Bellotti T, Raghavan M, Young BD, Saha V, Harrison CJ (2006) Complex genomic alterations and gene expression in acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21. Proc Natl Acad Sci USA 103:8167–8172

    Article  CAS  PubMed  Google Scholar 

  37. Sulong S, Moorman AV, Irving JA, Strefford JC, Konn ZJ, Case MC, Minto L, Barber KE, Parker H, Wright SL, Stewart AR, Bailey S, Bown NP, Hall AG, Harrison CJ (2009) A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups. Blood 113:100–107

    Article  CAS  PubMed  Google Scholar 

  38. Dear PH (2009) Copy-number variation: the end of the human genome? Trends Biotechnol 27:448–454

    Article  CAS  PubMed  Google Scholar 

  39. Shlien A, Tabori U, Marshall CR, Pienkowska M, Feuk L, Novokmet A, Nanda S, Druker H, Scherer SW, Malkin D (2008) Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome. Proc Natl Acad Sci USA 105:11264–11269

    Article  CAS  PubMed  Google Scholar 

  40. Dermitzakis ET, Stranger BE (2006) Genetic variation in human gene expression. Mamm Genome 17:503–508

    Article  PubMed  Google Scholar 

  41. Reymond A, Henrichsen CN, Harewood L, Merla G (2007) Side effects of genome structural changes. Curr Opin Genet Dev 17:381–386

    Article  CAS  PubMed  Google Scholar 

  42. Guryev V, Saar K, Adamovic T, Verheul M, van Heesch SA, Cook S, Pravenec M, Aitman T, Jacob H, Shull JD, Hubner N, Cuppen E (2008) Distribution and functional impact of DNA copy number variation in the rat. Nat Genet 40:538–545

    Article  CAS  PubMed  Google Scholar 

  43. Henrichsen CN, Vinckenbosch N, Zollner S, Chaignat E, Pradervand S, Schutz F, Ruedi M, Kaessmann H, Reymond A (2009) Segmental copy number variation shapes tissue transcriptomes. Nat Genet 41:424–429

    Article  CAS  PubMed  Google Scholar 

  44. Sexton T, Umlauf D, Kurukuti S, Fraser P (2007) The role of transcription factories in large-scale structure and dynamics of interphase chromatin. Semin Cell Dev Biol 18:691–697

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Jun Wan or Xiaojun Huang.

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Hong Yang and Chao Zhang contributed equally to this work.

Jun Wan and Xiaojun Huang contributed equally to this work.

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Yang, H., Zhang, C., Zhao, X. et al. Analysis of copy number variations of BS69 in multiple types of hematological malignancies. Ann Hematol 89, 959–964 (2010). https://doi.org/10.1007/s00277-010-0966-5

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