Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Relationship between expression of genes involved in cell cycle control and apoptosis in diffuse large B cell lymphoma: a preferential survivin–cyclin B link

Leukemia volume 16, pages 726–735 (2002)Cite this article

Abstract

Accumulating evidence suggests that lack of balance between proliferation and apoptosis may lead to clonal expansion and cancer emergence. In diffuse large B cell lymphoma (DLBCL), survivin expression by tumor cells has been recently described as a poor prognostic marker. We assessed the relationship between survivin gene up-regulation and several other factors involved in either cell cycle or apoptosis control. The expression of 34 genes from 27 cases of DLBCL with typical IPI factor-related poor prognostic outcome was analyzed by RNase protection assay. Using non-neoplastic tissues and low grade lymphomas as control, survivin expression was high in 80% of the cases without significant relation to patient overall survival (P = 0.64). However, the expression of several genes encoding for cell cycle inhibitors, cyclins, Bcl-2 or IAP family factors was significantly associated with the survivin up-regulation. Gene expression profiling showed that both survivin and cyclin B expression can define two subgroups of DLBCL: the previously described germinal center-like and activated B-like lymphomas, determined by protein expression analysis. We also identified a preferential survivin–cyclin B relationship (P = 0.017), suggesting that cyclin B over-expression, when linked to survivin over-expression in aggressive forms of lymphoma, might demonstrate a specific G2/M transition promotion.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA, Miller TP . Comparison of standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma N Engl J Med 1993 328: 1002–1006

    Article  CAS  PubMed  Google Scholar 

  2. Fisher RI . Diffuse large-cell lymphoma Ann Oncol 2000 11: S29–S33

    Article  Google Scholar 

  3. Shipp MA, Harrington DP, Andersen JR . The international non-Hodgkin's lymphoma prognostic factors project. A predictive model for aggressive non-Hodgkin's lymphoma N Engl J Med 1993 329: 987–994

    Article  Google Scholar 

  4. Winter JN . Prognostic indicators in diffuse, aggressive non-Hodgkin's lymphomas: regulators of growth fraction and programmed cell death Semin Oncol 1999 26: 26–33

    CAS  PubMed  Google Scholar 

  5. Moller MB, Ino Y, Gerdes AM, Skjodt K, Louis DN, Pedersen NT . Aberrations of the p53 pathway components p53, MDM2 and CDKN2A appear independent in diffuse large B cell lymphoma Leukemia 1999 13: 453–459

    Article  CAS  PubMed  Google Scholar 

  6. Moller MB, Kania PW, Ino Y, Gerdes AM, Nielsen O, Louis DN, Skjodt K, Pedersen NT . Frequent disruption of the RB1 pathway in diffuse large B cell lymphoma: prognostic significance of E2F-1 and p16INK4A Leukemia 2000 14: 898–904

    Article  CAS  PubMed  Google Scholar 

  7. Gronbaek K, de Nully Brown P, Moller MB, Nedergaard T, Ralfkiaer E, Moller P, Zeuthen J, Guldberg P . Concurrent disruption of p16INK4a and the ARF-p53 pathway predicts poor prognosis in aggressive non-Hodgkin's lymphoma Leukemia 2000 14: 1727–1735

    Article  CAS  PubMed  Google Scholar 

  8. Alizadeh AA, Staudt LM . Genomic-scale gene expression profiling of normal and malignant cells Curr Opin Immunol 2000 12: 219–225

    Article  CAS  PubMed  Google Scholar 

  9. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM . Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling Nature 2000 403: 503–511

    Article  CAS  PubMed  Google Scholar 

  10. Guo M, Hay BA . Cell proliferation and apoptosis Curr Opin Cell Biol 1999 11: 745–752

    Article  CAS  PubMed  Google Scholar 

  11. Korsmeyer SJ, Greenberg PD . Cancer. Tuning in on death programs Curr Opin Immunol 1998 10: 543–544

    Article  CAS  Google Scholar 

  12. Lowe SW, Lin AW . Apoptosis in cancer Carcinogenesis 2000 21: 485–495

    Article  CAS  PubMed  Google Scholar 

  13. Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE, Housman DE, Jacks T . p53 status and the efficacy of cancer therapy in vivo Science 1994 266: 807–810

    Article  CAS  PubMed  Google Scholar 

  14. Wilson WH, Teruya-Feldstein J, Fest T, Harris C, Steinberg SM, Jaffe ES, Raffeld M . Relationship of p53, bcl-2, and tumor proliferation to clinical drug resistance in non-Hodgkin's lymphomas Blood 1997 89: 601–609

    CAS  PubMed  Google Scholar 

  15. Schmitt CA, McCurrach ME, de Stanchina E, Wallace-Brodeur RR, Lowe SW . INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53 Genes Dev 1999 13: 2670–2677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Solary E, Droin N, Bettaieb A, Corcos L, Dimanche-Boitrel MT, Garrido C . Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies Leukemia 2000 14: 1833–1849

    Article  CAS  PubMed  Google Scholar 

  17. Evan G, Littlewood T . A matter of life and cell death Science 1998 281: 1317–1322

    Article  CAS  PubMed  Google Scholar 

  18. Harris AW, Strasser A, Elefanty AG, Bath ML, Cory S . Deregulation of cell survival in lymphomagenesis Leukemia 1997 11 (Suppl. 3): 383–384

    Google Scholar 

  19. Meijerink JP . t(14;18), a journey to eternity Leukemia 1997 11: 2175–2187

    Article  CAS  PubMed  Google Scholar 

  20. Innocente SA, Abrahamson JLA, Cogswell JP, Lee JM . p53 regulates a G2 checkpoint through cyclin B1 Proc Natl Acad Sci USA 1999 96: 2147–2152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Passalaris TM, Benanti JA, Gewin L, Kiyono T, Galloway DA . The G2 checkpoint is maintained by redundant pathways Mol Cell Biol 1999 19: 5872–5881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chan TA, Hwang PM, Hermeking H, Kinzler KW, Vogelstein B . Cooperative effects of genes controlling the G2/M checkpoint Genes Dev 2000 14: 1584–1588

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Korsmeyer SJ . BCL-2 gene family and the regulation of programmed cell death Cancer Res 1999 59: 1693s–1700s

    CAS  PubMed  Google Scholar 

  24. Los M, Herr I, Friesen C, Fulda S, Schulze-Osthoff K, Debatin KM . Cross-resistance of CD95- and drug-induced apoptosis as a consequence of deficient activation of caspases (ICE/Ced-3 Proteases) Blood 1997 90: 3118–3129

    CAS  PubMed  Google Scholar 

  25. Martinez-Lorenzo MJ, Gamen S, Etxeberria J, Lasierra P, Larrad L, Pineiro A, Anel A, Naval J, Alava MA . Resistance to apoptosis correlates with a highly proliferative phenotype and loss of Fas and CPP32 (caspase-3) expression in human leukemia cells Int J Cancer 1998 75: 473–481

    Article  CAS  PubMed  Google Scholar 

  26. Fadeel B, Orrenius S, Zhivotovsky B . The most unkindest cut of all: on the multiple roles of mammalian caspases Leukemia 2000 14: 1514–1525

    Article  CAS  PubMed  Google Scholar 

  27. Ambrosini G, Adida C, Altieri D . A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma Nat Med 1997 3: 917–921

    Article  CAS  PubMed  Google Scholar 

  28. Adida C, Haioun C, Gaulard P, Lepage E, Morel P, Briere J, Dombret H, Reyes F, Diebold J, Gisselbrecht C, Salles G, Altieri DC, Molina TJ . Prognostic significance of survivin expression in diffuse large B-cell lymphomas Blood 2000 96: 1921–1925

    CAS  PubMed  Google Scholar 

  29. Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC . Control of apoptosis and mitotic spindle checkpoint by survivin Nature 1998 396: 580–584

    CAS  PubMed  Google Scholar 

  30. Suzuki A, Ito T, Kawano H, Hayashida M, Hayasaki Y, Tsutomi Y, Akahane K, Nakano T, Miura M, Shiraki K . Survivin initiates procaspase 3/p21 complex formation as a result of interaction with Cdk4 to resist Fas-mediated cell death Oncogene 2000 19: 1346–1353

    Article  CAS  PubMed  Google Scholar 

  31. Skoufias DA, Mollinari C, Lacroix FB, Margolis RL . Human survivin is a kinetochore-associated passenger protein J Cell Biol 2000 151: 1575–1581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jaffe ES, Harris NL, Stein H, Vardiman JW . Pathology and genetics of tumors of haematopoietic and lymphoid tissues. World Health Organisation Classification of Tumors IARC Press: Lyon 2001

    Google Scholar 

  33. Lukes RJ, Collins RD . Immunologic characterization of human malignant lymphomas Cancer 1974 34: S1488–S1503

    Article  Google Scholar 

  34. Stansfeld AG, Diebold J, Kapanci Y, Kelenyi G, Lennert K, Mioduszewska O, Noel H, Rilke F, Sundstrom C, van Unnik JAM, Wright DH . Updated Kiel classification for lymphomas Lancet 1988 1: 292–298

    Article  CAS  PubMed  Google Scholar 

  35. Chomczynski P, Sacchi N . Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction Anal Biochem 1987 162: 156–159

    Article  CAS  PubMed  Google Scholar 

  36. Sambrook J, Fritsch EF, Maniatis T (eds). Synthesis of RNA probes by in vitro transcription of double-stranded DNA templates by bacteriophage DNA-dependant RNA polymerases Molecular Cloning: A Laboratory Manual, 2nd edn Cold Spring Harbor Laboratory: Cold Spring Harbor 1989 pp 10.27–10.37

    Google Scholar 

  37. Tayebi H, Kuttler F, Saas P, Lienard A, Petracca B, Lapierre V, Ferrand C, Fest T, Cahn JY, Blaise D, Kuentz M, Hervé P, Tiberghien P, Robinet E . Effect of granulocyte-colony stimulating factor (G-CSF) mobilisation on phenotypical and functional properties of immune cells Exp Hematol 2001 29: 458–470

    Article  CAS  PubMed  Google Scholar 

  38. Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, de Waard R, Leung C, Nouri-Shirazi M, Orazi A, Chaganti RS, Rothman P, Stall AM, Pandolfi PP, Dalla-Favera R . The BCL-6 proto-oncogene controls germinal center formation and Th2-type inflammation Nat Genet 1997 16: 161–170

    Article  CAS  PubMed  Google Scholar 

  39. Dent AL, Shaffer AL, Yu X, Allman D, Staudt LM . Control of inflammation, cytokine expression, and germinal center formation by BCL-6 Science 1997 276: 589–592

    Article  CAS  PubMed  Google Scholar 

  40. Dogan A, Bagdi E, Munson P, Isaacson PG . CD10 and BCL-6 expression in paraffin section of normal lymphoid tissue and B-cell lymphomas Am J Surg Pathol 2000 24: 846–852

    Article  CAS  PubMed  Google Scholar 

  41. Hermine O, Haioun C, Lepage E, d'Agay MF, Briere J, Lavignac C, Fillet G, Salles G, Marolleau JP, Diebold J, Reyas F, Gaulard P . Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin's lymphoma Blood 1996 87: 265–272

    CAS  PubMed  Google Scholar 

  42. Ichikawa A, Kinoshita T, Watanabe T, Kato H, Nagai H, Tsushita K, Saito H, Hotta T . Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma N Engl J Med 1997 337: 529–534

    Article  CAS  PubMed  Google Scholar 

  43. Miller TP, Grogan TM, Dahlberg S, Spier CM, Braziel RM, Banks PM, Foucar K, Kjeldsberg CR, Levy N, Nathwani BN . Prognostic significance of the Ki-67-associated proliferative antigen in aggressive non-Hodgkin's lymphomas: a prospective Southwest Oncology Group Trial Blood 1994 83: 1460–1466

    CAS  PubMed  Google Scholar 

  44. Shaulsky G, Goldfinger N, Peled A, Rotter V . Involvement of wild-type p53 in pre-B-cell differentiation in vitro Proc Natl Acad Sci USA 1991 88: 8982–8986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zuckerberg LR, Benedict WF, Arnold A, Dyson N, Harlow E, Harris NL . Expression of the retinoblastoma protein in low-grade B-cell lymphoma: relationship to cylin D1 Blood 1996 88: 268–276

    Google Scholar 

  46. Dowdy SF, Hinds PW, Louie K, Reed SI, Arnold A, Weinberg RA . Physical interaction of the retinoblastoma protein with the human D cyclins Cell 1993 73: 499–511

    Article  CAS  PubMed  Google Scholar 

  47. Daniel PT . Dissecting the pathways to death Leukemia 2000 14: 2035–2044

    Article  CAS  PubMed  Google Scholar 

  48. Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T, Reed JC . IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs Cancer Res 1998 58: 5315–5320

    CAS  PubMed  Google Scholar 

  49. Ito T, Shiraki K, Sugimoto K, Yamanaka T, Fujikawa K, Ito M, Takase K, Moriyama M, Kawano H, Hayashida M, Nakano T, Suzuki A . Survivin promotes cell proliferation in human hepatocellular carcinoma Hepatology 2000 31: 1080–1085

    Article  CAS  PubMed  Google Scholar 

  50. O'Connor DS, Grossman D, Plescia J, Li F, Zhang H, Villa A, Tognin S, Marchisio PC, Altieri DC . Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin Proc Natl Acad Sci USA 2000 97: 13103–13107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cogswell JP, Godlevski MM, Bonham M, Bisi J, Babis S . Upstream stimulatory factor regulates expression of the cell cycle-dependent cyclin B1 promoter Mol Cell Biol 1995 15: 2782–2790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Ligue Contre le Cancer du Doubs and AMGEN SA Company, Neuilly, France. We wish to thank Dr Frédéric Mauny (Département d'Information Médicale, Besançon) for providing his expertise in the statistical analysis.

Author information

Authors and Affiliations

  1. Institut d'Etude et de Transfert de Gènes (IETG), Centre Hospitalier Régional et Universitaire, Hôpital Jean Minjoz, Besançon, France

    F Kuttler, M-B Valnet-Rabier, C Mougin & T Fest

  2. Service d'anatomie pathologique, Centre Hospitalier Régional et Universitaire, Hôpital Jean Minjoz, Besançon, France

    M-B Valnet-Rabier & R Angonin

  3. Etablissement Français du Sang de Bourgogne Franche-Comté, Centre Hospitalier Régional et Universitaire, Hôpital Jean Minjoz, Besançon, France

    C Ferrand

  4. Service d'hématologie, Centre Hospitalier Régional et Universitaire, Hôpital Jean Minjoz, Besançon, France

    E Deconinck, J-Y Cahn & T Fest

  5. Laboratoire de Virologie, Centre Hospitalier Régional et Universitaire, Hôpital Jean Minjoz, Besançon, France

    C Mougin

Authors
  1. F Kuttler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M-B Valnet-Rabier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Angonin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Ferrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E Deconinck
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Mougin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J-Y Cahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T Fest
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kuttler, F., Valnet-Rabier, MB., Angonin, R. et al. Relationship between expression of genes involved in cell cycle control and apoptosis in diffuse large B cell lymphoma: a preferential survivin–cyclin B link. Leukemia 16, 726–735 (2002). https://doi.org/10.1038/sj.leu.2402427

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402427

Keywords

This article is cited by

Search

Advanced search

Quick links