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 Article
  • Published:

Lymphoma

A comprehensive genetic and histopathologic analysis identifies two subgroups of B-cell malignancies carrying a t(14;19)(q32;q13) or variant BCL3-translocation

Leukemia volume 21, pages 1532–1544 (2007)Cite this article

Abstract

The biologic and pathologic features of B-cell malignancies bearing a translocation t(14;19)(q32;q13) leading to a fusion of IGH and BCL3 are still poorly described. Herein we report the results of a comprehensive cytogenetic, fluorescence in situ hybridization (FISH), molecular and histopathological survey of a large series of B-cell malignancies with t(14;19) or variant translocations. A total of 56 B-cell malignancies with a FISH-proven BCL3 involvement were identified with the translocation partners being IGH (n=51), IGL (n=2), IGK (n=2) and a non-IG locus (n=1). Hierarchical clustering of chromosomal changes associated with the t(14;19) indicated the presence of two different groups of IG/BCL3-positive lymphatic neoplasias. The first group included 26 B-cell malignancies of various histologic subtypes containing a relatively high number of chromosomal changes and mostly mutated IgVH genes. This cluster displayed three cytogenetic branches, one with rearrangements in 7q, another with deletions in 17p and a third one with rearrangements in 1q and deletions in 6q and 13q. The second group included 19 cases, mostly diagnosed as B-cell chronic lymphocytic leukemia (B-CLL), and characterized by few additional chromosomal changes (e.g. trisomy 12) and unmutated IgVH genes. In conclusion, our study indicates that BCL3 translocations are not restricted to B-CLL but present in a heterogeneous group of B-cell malignancies.

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

Similar content being viewed by others

References

  1. McKeithan TW, Takimoto GS, Ohno H, Bjorling VS, Morgan R, Hecht BK et al. BCL3 rearrangements and t(14;19) in chronic lymphocytic leukemia and other B-cell malignancies: a molecular and cytogenetic study. Genes Chromosomes Cancer 1997; 20: 64–72.

    Article  CAS  PubMed  Google Scholar 

  2. Michaux L, Dierlamm J, Wlodarska I, Bours V, Van den Berghe H, Hagemeijer A . t(14;19)/BCL3 rearrangements in lymphoproliferative disorders: a review of 23 cases. Cancer Genet Cytogenet 1997; 94: 36–43.

    Article  CAS  PubMed  Google Scholar 

  3. Ueshima Y, Bird ML, Vardiman JW, Rowley JD . A 14;19 translocation in B-cell chronic lymphocytic leukemia: a new recurring chromosome aberration. Int J Cancer 1985; 36: 287–290.

    Article  CAS  PubMed  Google Scholar 

  4. Rayet B, Gelinas C . Aberrant rel/nfkb genes and activity in human cancer. Oncogene 1999; 18: 6938–6947.

    Article  CAS  PubMed  Google Scholar 

  5. McKeithan TW, Rowley JD, Shows TB, Diaz MO . Cloning of the chromosome translocation breakpoint junction of the t(14;19) in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 1987; 84: 9257–9260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ohno H, Takimoto G, McKeithan TW . The candidate proto-oncogene bcl-3 is related to genes implicated in cell lineage determination and cell cycle control. Cell 1990; 60: 991–997.

    Article  CAS  PubMed  Google Scholar 

  7. McDonnell TJ, Korsmeyer SJ . Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature 1991; 349: 254–256.

    Article  CAS  PubMed  Google Scholar 

  8. Ong ST, Hackbarth ML, Degenstein LC, Baunoch DA, Anastasi J, McKeithan TW . Lymphadenopathy, splenomegaly, and altered immunoglobulin production in BCL3 transgenic mice. Oncogene 1998; 16: 2333–2343.

    Article  CAS  PubMed  Google Scholar 

  9. Siebert R, Rosenwald A, Staudt LM, Morris SW . Molecular features of B-cell lymphoma. Curr Opin Oncol 2001; 13: 316–324.

    Article  CAS  PubMed  Google Scholar 

  10. Willis TG, Dyer MJ . The role of immunoglobulin translocations in the pathogenesis of B-cell malignancies. Blood 2000; 96: 808–822.

    CAS  PubMed  Google Scholar 

  11. Soma LA, Gollin SM, Remstein ED, Ketterling RP, Flynn HC, Rajasenan KK et al. Splenic small B-cell lymphoma with IGH/BCL3 translocation. Hum Pathol 2006; 37: 218–230.

    Article  CAS  PubMed  Google Scholar 

  12. Huh YO, Abruzzo LV, Rassidakis GZ, Parry-Jones N, Schlette E, Brito-Bapabulle V et al. The t(14;19)(q32;q13)-positive small B-cell leukaemia: a clinicopathologic and cytogenetic study of seven cases. Br J Haematol 2007; 136: 220–228.

    Article  CAS  PubMed  Google Scholar 

  13. Au WY, Horsman DE, Ohno H, Klasa RJ, Gascoyne RD . Bcl-3/IgH translocation (14;19)(q32;q13) in non-Hodgkin's lymphomas. Leuk Lymphoma 2002; 43: 813–816.

    Article  CAS  PubMed  Google Scholar 

  14. Martin-Subero JI, Wlodarska I, Bastard C, Picquenot JM, Hoppner J, Giefing M et al. Chromosomal rearrangements involving the BCL3 locus are recurrent in classical Hodgkin and peripheral T-cell lymphoma. Blood 2006; 108: 401–402, author reply 402–403.

    Article  CAS  PubMed  Google Scholar 

  15. Michaux L, Mecucci C, Stul M, Wlodarska I, Hernandez JM, Meeus P et al. BCL3 rearrangement and t(14;19)(q32;q13) in lymphoproliferative disorders. Genes Chromosomes Cancer 1996; 15: 38–47.

    Article  CAS  PubMed  Google Scholar 

  16. Sole F, Woessner S, Florensa L, Perez-Losada A, Bonet C, Besses C . A new case of t(14;19) (q32;q13) in a patient with follicular lymphoma in leukemic phase. Cancer Genet Cytogenet 1994; 75: 72–73.

    Article  CAS  PubMed  Google Scholar 

  17. van Krieken JH, McKeithan TW, Raghoebier S, Medeiros LJ, Kluin PM, Raffeld M . Chromosomal translocation t(14;19) as indicated by bcl-3 rearrangement is a rare phenomenon in non-Hodgkin's lymphoma and chronic lymphocytic leukemia: a molecular genetic analysis of 176 cases. Leukemia 1990; 4: 811–812.

    CAS  PubMed  Google Scholar 

  18. Baro C, Salido M, Domingo A, Granada I, Colomo L, Serrano S et al. Translocation t(9;14)(p13;q32) in cases of splenic marginal zone lymphoma. Haematologica 2006; 91: 1289–1291.

    PubMed  Google Scholar 

  19. Yamamoto K, Nakamura Y, Arai H, Aoyagi M, Saito K, Furusawa S et al. Translocation (14;19)(q32;q13) detected by spectral karyotyping and lack of BCL3 rearrangement in CD5-positive B-cell lymphoma associated with hemophagocytic syndrome. Cancer Genet Cytogenet 2001; 130: 38–41.

    Article  CAS  PubMed  Google Scholar 

  20. Sonoki T, Harder L, Horsman DE, Karran L, Taniguchi I, Willis TG et al. Cyclin D3 is a target gene of t(6;14)(p21.1;q32.3) of mature B-cell malignancies. Blood 2001; 98: 2837–2844.

    Article  CAS  PubMed  Google Scholar 

  21. Martin-Subero JI, Harder L, Gesk S, Schlegelberger B, Grote W, Martinez-Climent JA et al. Interphase FISH assays for the detection of translocations with breakpoints in immunoglobulin light chain loci. Int J Cancer 2002; 98: 470–474.

    Article  CAS  PubMed  Google Scholar 

  22. Satterwhite E, Sonoki T, Willis TG, Harder L, Nowak R, Arriola EL et al. The BCL11 gene family: involvement of BCL11A in lymphoid malignancies. Blood 2001; 98: 3413–3420.

    Article  CAS  PubMed  Google Scholar 

  23. Küppers R, Sonoki T, Satterwhite E, Gesk S, Harder L, Oscier DG et al. Lack of somatic hypermutation of IG V(H) genes in lymphoid malignancies with t(2;14)(p13;q32) translocation involving the BCL11A gene. Leukemia 2002; 16: 937–939.

    Article  PubMed  Google Scholar 

  24. Ritgen M, Lange A, Stilgenbauer S, Dohner H, Bretscher C, Bosse H et al. Unmutated immunoglobulin variable heavy-chain gene status remains an adverse prognostic factor after autologous stem cell transplantation for chronic lymphocytic leukemia. Blood 2003; 101: 2049–2053.

    Article  CAS  PubMed  Google Scholar 

  25. Saez B, Martin-Subero JI, Guillen-Grima F, Odero MD, Prosper F, Cigudosa JC et al. Chromosomal abnormalities clustering in multiple myeloma reveals cytogenetic subgroups with nonrandom acquisition of chromosomal changes. Leukemia 2004; 18: 654–657.

    Article  CAS  PubMed  Google Scholar 

  26. Matutes E, Oscier D, Garcia-Marco J, Ellis J, Copplestone A, Gillingham R et al. Trisomy 12 defines a group of CLL with atypical morphology: correlation between cytogenetic, clinical and laboratory features in 544 patients. Br J Haematol 1996; 92: 382–388.

    Article  CAS  PubMed  Google Scholar 

  27. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK . Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94: 1848–1854.

    CAS  PubMed  Google Scholar 

  28. Davis ZA, Orchard JA, Corcoran MM, Oscier DG . Divergence from the germ-line sequence in unmutated chronic lymphocytic leukemia is due to somatic mutation rather than polymorphisms. Blood 2003; 102: 3075.

    Article  CAS  PubMed  Google Scholar 

  29. Ghia P, Stamatopoulos K, Belessi C, Moreno C, Stilgenbauer S, Stevenson F et al. ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia. Leukemia 2007; 21: 1–3.

    Article  CAS  PubMed  Google Scholar 

  30. Harris NL, Jaffe ES, Vardiman JW, Stein H, Diebold J, M-HH K et al. WHO classification of tumors of haematopoietic and lymphoid tissue: Introduction. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organization Classification of Tumors Pathology and Genetics of Tumors of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press, 2001, 12–13.

    Google Scholar 

  31. Hummel M, Bentink S, Berger H, Klapper W, Wessendorf S, Barth TF et al. A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling. N Engl J Med 2006; 354: 2419–2430.

    Article  CAS  PubMed  Google Scholar 

  32. Bloomfield CD, Arthur DC, Frizzera G, Levine EG, Peterson BA, Gajl-Peczalska KJ . Nonrandom chromosome abnormalities in lymphoma. Cancer Res 1983; 43: 2975–2984.

    CAS  PubMed  Google Scholar 

  33. Canoz O, Rassidakis GZ, Admirand JH, Medeiros LJ . Immunohistochemical detection of BCL-3 in lymphoid neoplasms: a survey of 353 cases. Mod Pathol 2004; 17: 911–917.

    Article  PubMed  Google Scholar 

  34. Mathas S, Johrens K, Joos S, Lietz A, Hummel F, Janz M et al. Elevated NF-kappaB p50 complex formation and Bcl-3 expression in classical Hodgkin, anaplastic large-cell, and other peripheral T-cell lymphomas. Blood 2005; 106: 4287–4293.

    Article  CAS  PubMed  Google Scholar 

  35. Akasaka T, Ueda C, Kurata M, Akasaka H, Yamabe H, Uchiyama T et al. Nonimmunoglobulin (non-Ig)/BCL6 gene fusion in diffuse large B-cell lymphoma results in worse prognosis than Ig/BCL6. Blood 2000; 96: 2907–2909.

    CAS  PubMed  Google Scholar 

  36. Bertrand P, Maisonneuve C, Maingonnat C, M.N. C, J.M. P, Tilly H et al. Preliminary study of c-MYC rearrangements with non-IG partners in B-cell lymphomas. Ann Oncol 2005; 16: v80.

    Google Scholar 

  37. Dunphy CH, van Deventer HW, Carder KJ, Rao KW, Dent GA . Mature B-cell acute lymphoblastic leukemia with associated translocations (14;18)(q32;q21) and (8;9)(q24;p13). A Burkitt variant? Arch Pathol Lab Med 2003; 127: 610–613.

    PubMed  Google Scholar 

  38. Chapiro E, Russell L, Radford-Weiss I, Bastard C, Lessard M, Struski S et al. Overexpression of CEBPA resulting from the translocation t(14;19)(q32;q13) of human precursor B acute lymphoblastic leukemia. Blood 2006; 108: 3560–3563.

    Article  CAS  PubMed  Google Scholar 

  39. Akasaka T, Balasas T, Russell LJ, Sugimoto KJ, Majid A, Walewska R et al. Five members of the CEBP transcription factor family are targeted by recurrent IGH-translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blood 2007; 109: 3451–3461.

    Article  CAS  PubMed  Google Scholar 

  40. Lenz G, Nagel I, Siebert R, Roschke AV, Sanger W, Wright GW . Immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B-cell lymphoma. J Exp Med 2007; 204: 633–643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Schlette E, Rassidakis GZ, Canoz O, Medeiros LJ . Expression of bcl-3 in chronic lymphocytic leukemia correlates with trisomy 12 and abnormalities of chromosome 19. Am J Clin Pathol 2005; 123: 465–471.

    Article  PubMed  Google Scholar 

  42. Oscier DG, Gardiner A, Mould S . Structural abnormalities of chromosome 7q in chronic lymphoproliferative disorders. Cancer Genet Cytogenet 1996; 92: 24–27.

    Article  CAS  PubMed  Google Scholar 

  43. Boonstra R, Bosga-Bouwer A, van Imhoff GW, Krause V, Palmer M, Coupland RW et al. Splenic marginal zone lymphomas presenting with splenomegaly and typical immunophenotype are characterized by allelic loss in 7q31-32. Mod Pathol 2003; 16: 1210–1217.

    Article  PubMed  Google Scholar 

  44. 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  PubMed  PubMed Central  Google Scholar 

  45. Tilly H, Rossi A, Stamatoullas A, Lenormand B, Bigorgne C, Kunlin A et al. Prognostic value of chromosomal abnormalities in follicular lymphoma. Blood 1994; 84: 1043–1049.

    CAS  PubMed  Google Scholar 

  46. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1910–1916.

    Article  CAS  PubMed  Google Scholar 

  47. Vasconcelos Y, Davi F, Levy V, Oppezzo P, Magnac C, Michel A et al. Binet's staging system and VH genes are independent but complementary prognostic indicators in chronic lymphocytic leukemia. J Clin Oncol 2003; 21: 3928–3932.

    Article  CAS  PubMed  Google Scholar 

  48. Ghiotto F, Fais F, Valetto A, Albesiano E, Hashimoto S, Dono M et al. Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia. J Clin Invest 2004; 113: 1008–1016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Stamatopoulos K, Belessi C, Moreno C, Boudjograh M, Guida G, Smilevska T et al. Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: Pathogenetic implications and clinical correlations. Blood 2007; 109: 259–270.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Claudia Becher, Dorit Schuster, Magret Ratjen and Reina Zühlke-Jenisch (Institute of Human Genetics, Kiel, Germany) for their excellent technical assistance. This work was supported by the Deutsche Krebshilfe, the Fund for Scientific Research of Flanders (FWO-Vlaanderen, Grant No. G.0338.01), the Leukaemia Research Fund (UK) and the Marató de TV3 (Càncer, 2.005).

Author information

Author notes

  1. J I Martín-Subero, R Ibbotson, W Klapper and L Michaux: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel, Christian-Albrechts University, Kiel, Germany

    J I Martín-Subero, S Gesk, L Harder & R Siebert

  2. Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK

    R Ibbotson, A Gardiner & D Oscier

  3. Institute of Hematopathology, University Hospital Schleswig-Holstein Campus Kiel, Christian-Albrechts University, Kiel, Germany

    W Klapper & H-H Wacker

  4. Center for Human Genetics, Catholic University of Leuven, Leuven, Belgium

    L Michaux & I Wlodarska

  5. Service d'Hématologie Biologique, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France

    E Callet-Bauchu & P Felman

  6. Service d'Anatomie Pathologique, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France

    F Berger

  7. Department of Genetics, University of Navarra, Pamplona, Spain

    M J Calasanz

  8. Department of Morphology and Molecular Pathology, Catholic University of Leuven, Leuven, Belgium

    C De Wolf-Peeters

  9. MRC Toxicology Unit, Leicester University, Leicester, UK

    M J Dyer & A Majid

  10. Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, Canada

    R D Gascoyne & D E Horsman

  11. Second Medical Department, University Hospital Schleswig-Holstein Campus Kiel, Christian-Albrechts University, Kiel, Germany

    M Kneba & M Ritgen

  12. Institute for Cell Biology (Tumor Research), University of Duisburg-Essen, Medical School, Essen, Germany

    R Küppers

  13. Section of Haemato-oncology, Royal Marsden Hospital/Institute of Cancer Research, London & Surrey, UK

    N Parry-Jones

  14. Laboratori de Citogen,

    M Salido & F Solé

  15. è,

    M Salido & F Solé

  16. tica i Biologia Molecular, Servei de Patologia, Hospital del Mar, Barcelona, Spain

    M Salido & F Solé

  17. Praxis für Humangenetik, Berlin, Germany

    G Thiel

Authors
  1. J I Martín-Subero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Ibbotson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W Klapper
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Michaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E Callet-Bauchu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F Berger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M J Calasanz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C De Wolf-Peeters
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M J Dyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. P Felman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A Gardiner
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. R D Gascoyne
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. S Gesk
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. L Harder
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. D E Horsman
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. M Kneba
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. R Küppers
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. A Majid
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. N Parry-Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. M Ritgen
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. M Salido
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. F Solé
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. G Thiel
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. H-H Wacker
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. D Oscier
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. I Wlodarska
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. R Siebert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R Siebert.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martín-Subero, J., Ibbotson, R., Klapper, W. et al. A comprehensive genetic and histopathologic analysis identifies two subgroups of B-cell malignancies carrying a t(14;19)(q32;q13) or variant BCL3-translocation. Leukemia 21, 1532–1544 (2007). https://doi.org/10.1038/sj.leu.2404695

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404695

Keywords

This article is cited by

Search

Advanced search

Quick links