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:

Lymphoma

Translocation t(14;18) and gain of chromosome 18/BCL2: effects on BCL2 expression and apoptosis in B-cell non-Hodgkin's lymphomas

Leukemia volume 19, pages 2313–2323 (2005)Cite this article

Abstract

Gain of chromosome 18q and translocation t(14;18) are] frequently found in B-cell non-Hodgkin's lymphomas (B-NHL). Increased BCL2 transcription and BCL2 protein expression have been suggested to be the result of the gain. We utilized FISH, PCR and array CGH to study BCL2 and chromosome 18 copy number changes and rearrangements in 93 cases of B-NHL. BCL2 protein was expressed in >75% of the tumor cells in 92% of the cases by immunohistochemistry. Gain of BCL2 was associated with a 25% increase in BCL2 expression levels (immunoblotting), whereas t(14;18) resulted in a 55% increase in BCL2 levels compared to cases without BCL2 alterations. The tumor cell (spontaneous) apoptotic fractions were similar for the cases with different BCL2 genotypes. However, the normal cell apoptotic fractions were higher for the tumors with t(14;18) compared to the tumors without BCL2 alterations, while the tumors with gain of BCL2 only showed intermediate levels. Low-level gains of parts of chromosome 18 were found in 14 of the 38 B-NHL cases with t(14;18), with a consensus region 18pter-q21.33 that did not include the BCL2 gene. The 11 cases with 18q gain only showed a consensus region encompassing 18q21.2–18q21.32 and 18q21.33, which contain PMAIP1/MALT1 and BCL2, respectively.

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 4
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM . Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 1984; 226: 1097–1099.

    Article  CAS  Google Scholar 

  2. Yunis JJ, Frizzera G, Oken MM, McKenna J, Theologides A, Arnesen M . Multiple recurrent genomic defects in follicular lymphoma. A possible model for cancer. N Engl J Med 1987; 316: 79–84.

    Article  CAS  Google Scholar 

  3. Weiss LM, Warnke RA, Sklar J, Cleary ML . Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas. N Engl J Med 1987; 317: 1185–1189.

    Article  CAS  Google Scholar 

  4. Jacobson JO, Wilkes BM, Kwaiatkowski DJ, Medeiros LJ, Aisenberg AC, Harris NL . BCL-2 rearrangements in de novo diffuse large cell lymphoma. Association with distinctive clinical features. Cancer 2003; 72: 231–236.

    Article  Google Scholar 

  5. Vaux DL, Cory S, Adams JM . Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988; 335: 440–442.

    Article  CAS  Google Scholar 

  6. McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U, McKearn JP et al. BCL-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 1989; 57: 79–88.

    Article  CAS  Google Scholar 

  7. Monni O, Joensuu H, Franssila K, Knuutila S . DNA copy number changes in diffuse large B-cell lymphoma – comparative genomic hybridization study. Blood 1996; 87: 5269–5278.

    CAS  PubMed  Google Scholar 

  8. Rao PH, Houldsworth J, Dyomina K, Parsa NZ, Cigudosa JC, Louie DC et al. Chromosomal and gene amplification in diffuse large B-cell lymphoma. Blood 1998; 92: 234–240.

    CAS  PubMed  Google Scholar 

  9. Berglund M, Enblad G, Flordal E, Lui WO, Backlin C, Thunberg U et al. Chromosomal imbalances in diffuse large B-cell lymphoma detected by comparative genomic hybridization. Mod Pathol 2002; 15: 807–816.

    Article  Google Scholar 

  10. Bentz M, Werner CA, Döhner H, Joos S, Barth TFE, Siebert R et al. High incidence of chromosomal imbalances and gene amplifications in the classical follicular variant of follicle center lymphoma. Blood 1996; 88: 1437–1444.

    CAS  PubMed  Google Scholar 

  11. Avet-Loiseau H, Vigier M, Moreau A, Mellerin MP, Gaillard F, Harousseau JL et al. Comparative genomic hybridization detects genomic abnormalities in 80% of follicular lymphomas. Br J Haematol 1997; 97: 119–122.

    Article  CAS  Google Scholar 

  12. Allen JE, Hough RE, Goepel JR, Bottomley S, Wilson GA, Alcock HE et al. Identification of novel regions of amplification and deletion within mantle cell lymphoma DNA by comparative genomic hybridization. Br J Haematol 2002; 116: 291–298.

    Article  CAS  Google Scholar 

  13. Dierlamm J, Rosenberg C, Stul M, Pittaluga S, Wlodarska I, Michaux L et al. Characteristic pattern of chromosomal gains and losses in marginal zone B cell lymphoma detected by comparative genomic hybridization. Leukemia 1997; 11: 747–758.

    Article  CAS  Google Scholar 

  14. Bentz M, Huck K, du Manoir S, Joos S, Werner CA, Fischer K et al. Comparative genomic hybridization in chronic B-cell leukemias shows a high incidence of chromosomal gains and losses. Blood 1995; 85: 3610–3618.

    CAS  PubMed  Google Scholar 

  15. Stokke T, DeAngelis P, Smedshammer L, Galteland E, Steen HB, Smeland EB et al. Loss of chromosome 11q21–23.1 and 17p and gain of chromosome 6p are independent prognostic indicators in B-cell non-Hodgkin's Lymphoma. Br J Cancer 2001; 85: 1900–1913.

    Article  CAS  Google Scholar 

  16. Viardot A, Möller P, Högel J, Werner K, Mechtersheimer G, Ho AD et al. Clinicopathologic correlations of genomic gains and losses in follicular lymphoma. J Clin Oncol 2002; 20: 4523–4530.

    Article  Google Scholar 

  17. Horsman DE, Connors JM, Pantzar T, Gascoyne RD . Analysis of secondary chromosomal alterations in 165 cases of follicular lymphoma with t(14;18). Genes Chromosomes Cancer 2001; 30: 375–382.

    Article  CAS  Google Scholar 

  18. Armitage JO, Sanger WG, Weisenburger DD, Harrington DS, Linder J, Bierman PJ et al. Correlation of secondary cytogenetic abnormalities with histologic appearance in Non-Hodgkin's lymphomas bearing t(14;18)(q32;q21). J Natl Cancer Institute 1988; 80: 576–580.

    Article  CAS  Google Scholar 

  19. Monni O, Joensuu H, Franssila K, Klefstrom J, Alitalo K, Knuutila S . BCL2 overexpression associated with chromosomal amplification in diffuse large B-cell lymphoma. Blood 1997; 90: 1168–1174.

    CAS  PubMed  Google Scholar 

  20. Sanchez-Izquierdo D, Buchonnet G, Siebert R, Gascoyne RD, Climent J, Karran L et al. MALT1 is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma. Blood 2003; 101: 4539–4546.

    Article  CAS  Google Scholar 

  21. Martinez-Climent JA, Alizadeh AA, Segraves R, Blesa D, Rubio-Moscardo F, Albertson DG et al. Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA copy number and gene expression alterations. Blood 2003; 101: 3109–3117.

    Article  CAS  Google Scholar 

  22. Ott G, Katzenberger T, Greiner A, Kalla J, Rosenwald A, Heinrich U et al. The t(11;18)(q21;q21) chromosome translocation is a frequent and specific aberration in low-grade but not high-grade malignant non-Hodgkin's lymphomas of the mucosa-associated lymphoid tissue (MALT−) type. Cancer Res 1997; 57: 3944–3948.

    CAS  PubMed  Google Scholar 

  23. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–511.

    Article  CAS  Google Scholar 

  24. Stokke T, Holte H, Smedshammer L, Smeland EB, Kaalhus O, Steen HB . Proliferation and apoptosis in malignant and normal cells in B-cell non-Hodgkin's lymphomas. Br J Cancer 1998; 7: 1832–1838.

    Article  Google Scholar 

  25. Stokke T, Galteland E, Holte H, Smedshammer L, Suo Z, Smeland EB et al. Oncogenic aberrations in the p53 pathway are associated with a high S phase fraction and poor patient survival in B-cell Non-Hodgkin's lymphoma. Int J Cancer 2000; 89: 313–324.

    Article  CAS  Google Scholar 

  26. Akasaka T, Akasaka H, Yonetani N, Ohno H, Yamabe H, Fukuhara S et al. Refinement of the BCL2/immunoglobulin heavy chain fusion gene in t(14;18)(q32;q21) by polymerase chain reaction amplification for long targets. Genes Chromosomes Cancer 1998; 21: 17–29.

    Article  CAS  Google Scholar 

  27. Galteland E, Holte H, Stokke T . c-MYC, RB-1, TP53, and centromere 8 and 17 copy number in B-cell non-Hodgkin's lymphomas assessed by dual-color fluorescence in situ hybridisation. Cytometry 1999; 38: 53–60.

    Article  CAS  Google Scholar 

  28. Galteland E, Smedshammer L, Suo Z, DeAngelis P, Stokke T . Proliferation-dependent expression and phosphorylation of pRB in B cell non-Hodgkin's lymphomas: dependence on RB1 copy number. Leukemia 2002; 16: 1549–1555.

    Article  CAS  Google Scholar 

  29. De Angelis PM, Clausen OP, Schjolberg A, Stokke T . Chromosomal gains and losses in primary colorectal carcinomas detected by CGH and their associations with tumour DNA ploidy, genotypes and phenotypes. Br J Cancer 1999; 80: 526–535.

    Article  CAS  Google Scholar 

  30. Osoegawa K, Mammoser AG, Wu C, Frengen E, Zeng C, Catanese JJ et al. A bacterial artificial chromosome library for sequencing the complete human genome. Genome Res 2001; 11: 483–496.

    Article  CAS  Google Scholar 

  31. Fiegler H, Carr P, Douglas EJ, Burford DC, Hunt S, Smith J et al. DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones. Genes Chromosomes Cancer 2003; 36: 361–374.

    Article  CAS  Google Scholar 

  32. Wang J, Meza-Zepeda LA, Kresse SH, Myklebost O . M-CGH: Analysing microarray-based CGH experiments. BMC Bioinformatics 2004; 5: 74.

    Article  CAS  Google Scholar 

  33. Holte H, Suo Z, Smeland EB, Kvaløy S, Langholm R, Stokke T . The prognostic value of lymphoma-specific S-phase compared with other cell proliferation markers. Acta Oncol 1999; 38: 495–503.

    Article  CAS  Google Scholar 

  34. Lømo J, Smeland EB, Krajewski S, Reed JC, Blomhoff HK . Expression of the Bcl-2 homologue Mcl-1 correlates with survival of peripheral blood B lymphocytes. Cancer Res 1996; 56: 40–43.

    PubMed  Google Scholar 

  35. Igney FH, Krammer PH . Death and anti-death: tumor resistance to apoptosis. Nat Rev Cancer 2002; 2: 277–288.

    Article  CAS  Google Scholar 

  36. Ghia P, Boussiotis VA, Schultze JL, Cardoso AA, Dorfman DM, Gribben JG et al. Unbalanced expression of bcl-2 family proteins in follicular lymphoma: contribution of CD40 signaling in promoting survival. Blood 1998; 91: 244–251.

    CAS  PubMed  Google Scholar 

  37. Karin M, Lin A . NF-kappa B at the crossroads of life and death. Nat Immunol 2002; 3: 221–227.

    Article  CAS  Google Scholar 

  38. Bea S, Colomo L, Lopez-Guillermo A, Salaverria I, Puig X, Pinyol M et al. Clinicopathologic significance and prognostic value of chromosomal imbalances in diffuse large B-cell lymphomas. J Clinical Oncol 2004; 22: 3498–3506.

    Article  CAS  Google Scholar 

  39. Stokke T, Smeland EB, Kvaløy S, Holte H . Tumor cell proliferation, but not apoptosis, predicts survival in B-cell non-Hodgkins lymphomas. Br J Cancer 1998; 77: 1839–1841.

    Article  CAS  Google Scholar 

  40. Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. New Engl J Med 2004; 351: 2159–2169.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by The Norwegian Cancer Society and The University of Oslo (EMBIO)

Author information

Authors and Affiliations

  1. Department of Radiation Biology, The Norwegian Radium Hospital, Oslo, Norway

    E Galteland, D H Svendsrud, L Smedshammer & T Stokke

  2. Department of Immunology, The Norwegian Radium Hospital, Oslo, Norway

    E A Sivertsen

  3. Department of Tumor Biology, The Norwegian Radium Hospital, Oslo, Norway

    S H Kresse, L A Meza-Zepeda & O Myklebost

  4. Department for Molecular Biosciences, University of Oslo, Oslo, Norway

    L A Meza-Zepeda & O Myklebost

  5. Department of Pathology, The Norwegian Radium Hospital, Oslo, Norway

    Z Suo

  6. Cold Spring Harbor Laboratory, Genome Research Center, Woodbury, NY, USA

    D Mu

  7. Institute of Pathology, Rikshospitalet, Oslo, Norway

    P M DeAngelis

Authors
  1. E Galteland
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E A Sivertsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D H Svendsrud
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Smedshammer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S H Kresse
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L A Meza-Zepeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. O Myklebost
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Z Suo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D Mu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. P M DeAngelis
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. T Stokke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Stokke.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Galteland, E., Sivertsen, E., Svendsrud, D. et al. Translocation t(14;18) and gain of chromosome 18/BCL2: effects on BCL2 expression and apoptosis in B-cell non-Hodgkin's lymphomas. Leukemia 19, 2313–2323 (2005). https://doi.org/10.1038/sj.leu.2403954

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403954

Keywords

This article is cited by

Search

Advanced search

Quick links