Skip to main content

Advertisement

Log in

The molecular biology of B-cell lymphoma: Clinicopathologic implications

  • Leading Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Summary

Nonrandom chromosomal translocations like the t(14;18), t(8;14), and t(11;14) are found in distinct types of B-cell malignancies. Recent molecular studies concerning their structure and origin showed that many translocations occur in early precursor B cells and may be interpreted as aberrant immunoglobulin gene rearrangements. The available data from in vitro experiments, transgenic mice, and normal human individuals indicate that these translocations are essential but insufficient for full tumorigenesis. The consequent “multi-hit” concept might have important implications for the detection of minimal residual disease using the polymerase chain reaction for these translocations. The strong associations with specific types of lymphomas underline their differences in histogenetic origin. Thus, based on differences inbcl-1 andbcl-2 rearrangements, molecular analysis may help to distinguish follicular lymphoma from diffuse centrocytic lymphoma and chronic lymphocytic leukemia. Furthermore, based on differences inbcl-2 and c-myc rearrangements, subtypes of de novo centroblastic lymphoma can be distinguished that have striking differences in biological behavior, especially nodal versus extranodal presentation. Therefore, future studies will show an increasing clinical relevance of molecular analysis in B-cell neoplasia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Adachi M, Cossman J, Longo D, Croce CM, Tsujimoto Y (1989) Variant translocation of thebcl-2 gene to immunoglobulin lambda light chain gene in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 86: 2771–2774

    PubMed  Google Scholar 

  2. Aisenberg AC, Wilkes BM, Jacobson JO (1988) Thebcl-2 gene is rearranged in many diffuse B-cell lymphomas. Blood 71: 969–972

    PubMed  Google Scholar 

  3. Anagnostopoulos I, Herbst H, Niedobitek G, Stein H (1989) Demonstration of monoclonal EBV genomes in Hodgkin's disease and Kl-1-positive anaplastic large cell lymphoma by combined Southern blot and in situ hybridization. Blood 74: 810–816

    PubMed  Google Scholar 

  4. Armitage JO, Sanger WG, Weisenburger DD, Harrington DS, Linder J, Bierman PJ, Vose JM, Purtilo DT (1988) Correlation of secondary cytogenetic abnormalities with histologic appearance in non-Hodgkin's lymphomas bearing t(14;18)(q32;q21). JNCI 80: 576–580

    PubMed  Google Scholar 

  5. Bertoli LF, Kubagawa H, Borzillo GV, Burrows PD, Schreeder MT, Carroll AJ, Cooper MD (1988) Bone marrow origin of B-cell lymphoma. Blood 72: 94–101

    PubMed  Google Scholar 

  6. Bird J, Galili N, Link M, Stites D, Sklar J (1988) Continuing rearrangement but absence of somatic hypermutation in immunoglobulin genes of human B cell precursor leukemia. J Exp Med 168: 229–245

    PubMed  Google Scholar 

  7. Bird ML, Ueshima Y, Rowley JD, Haren JM, Vardiman JW (1989) Chromosome abnormalities in B cell chronic lymphocytic leukemia and their clinical correlations. Leukemia 3: 182–191

    PubMed  Google Scholar 

  8. Calame K (1985) Mechanisms that regulate immunoglobulin gene expression. Annu Rev Immunol 3: 159–195

    PubMed  Google Scholar 

  9. Chan JKC, Ng CS, Isaacson PG (1990) Relationship between high-grade lymphoma and low-grade B-cell mucosa-associated lymphoid tissue lymphoma (MALToma) of the stomach. Am J Pathol 136: 1153–1164

    PubMed  Google Scholar 

  10. Cleary ML, Galili N, Sklar J (1986) Detection of a second t (14;18) breakpoint cluster region in human follicular lymphomas. J Exp Med 315: 320

    Google Scholar 

  11. Cleary ML, Galili N, Trela M, Levy R, Sklar J (1988) Single cell origin of bigenotypic and biphenotypic B cell proliferations in human follicular lymphoma. J Exp Med 167: 582–597

    PubMed  Google Scholar 

  12. Cleary ML, Sklar J (1985) Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18. Proc Natl Acad Sci USA 82: 7439–7443

    PubMed  Google Scholar 

  13. Cory S, Adams JM (1988) Transgenic mice and oncogenesis. Annu Rev Immunol 6: 25–48

    PubMed  Google Scholar 

  14. de Jong D, Voetdijk BMH, Beverstock GC, Ommen van GJB, Willemze R, Kluin PM (1988) Activation of the c-myc oncogene in a precursor-B-cell blast crisis of follicular lymphoma, presenting as composite lymphoma. N Engl J Med 318: 1373–1378

    PubMed  Google Scholar 

  15. de Jong D, Voetdijk BMH, Ommen van GJB, Kluin PM (1989) Alterations in immunoglobulin genes reveal the origin and evolution of monotypic and bitypic B cell lymphomas. Am J Pathol 134: 1233–1242

    PubMed  Google Scholar 

  16. de Jong D, Voetdijk BMH, Ommen van GJB, Kluin-Nelemans JC, Beverstock GC, Kluin PM (1989) Translocation t(14;18) in B cell lymphomas as a cause for defective immunoglobulin production. J Exp Med 169: 613–624

    PubMed  Google Scholar 

  17. Delia D, Borrello MG, Berti E, Pierotti MA, Biassoni D, Gianotti R, Alessi E, Rizzetti MG, Caputo R, Delia Porta G (1989) Clonal immunoglobulin gene rearrangements and normal T-cell receptor,bcl-2, and c-myc genes in primary cutaneous B-cell lymphomas. Cancer Res 49: 4901–4905

    PubMed  Google Scholar 

  18. Facer CA, Playfair JHL (1989) Malaria, Epstein-Barr virus, and the genesis of lymphomas. Adv Cancer Res 53: 33–72

    PubMed  Google Scholar 

  19. Falini B, Pileri S, Stein H, Dieneman D, Dallenbach F, Delsol G, Minelli O, Poggi S, Martelli MF, Pallesen G, Palestro G (1990) Variable expression of leucocyte-common (CD45) antigen in CD30 (Kil)-positive anaplastic large-cell lymphoma: implications for the differential diagnosis between lymphoid and nonlymphoid malignancies. Hum Pathol 21: 624–629

    PubMed  Google Scholar 

  20. Fifth International workshop on chromosomes in leukemia/lymphoma (1987) Correlation of chromosome abnormalities with histologic and immunologic characteristics in non-Hodgkin's lymphoma and adult T-cell lymphoma. Blood 70: 1554–1564

    Google Scholar 

  21. Fishleder AJ, Tubbs RR, Hesse B, Levine HB (1987) Uniform detection of immunoglobulin gene rearrangement in benign lymphoepithelial lesions. N Engl J Med 316: 1118–1121

    PubMed  Google Scholar 

  22. French DL, Laskov R, Scharff MD (1989) The role of somatic hypermutation in the generation of antibody diversity. Science 244: 1152–1157

    PubMed  Google Scholar 

  23. Fulop GM, Phillips RA (1990) The scid mutation in mice causes a general defect in DNA repair. Nature 347: 479–482

    PubMed  Google Scholar 

  24. Gauwerky CE, Haluska FG, Tsujimoto Y, Nowell PC, Croce CM (1988) Evolution of B-cell malignancy: pre-B-cell leukemia resulting frommyc activation in a B-cell neoplasm with a rearrangedbcl-2 gene. Proc Natl Acad Sci USA 85: 8548–8552

    PubMed  Google Scholar 

  25. Gauwerky CE, Hoxie J, Nowell PC, Croce CM (1988) Pre-B-cell leukemia with a t(8;14) and a t(14;18) translocation is preceded by follicular lymphoma. Oncogene 2: 431–435

    PubMed  Google Scholar 

  26. Graninger W, Seto M, Boutain B, Goldman P, Korsmeyer SJ (1987) Expression ofbcl-2 andbcl-2-Ig fusion transcripts in normal and neoplastic cells. J Clin Invest 80: 1512–1515

    PubMed  Google Scholar 

  27. Herbst H, Niedobitek G, Kneba M, Hummel M, Finn T, Anagnostopoulos I, Bergholz M, Krieger G, Stein H (1990) High incidence of Epstein-Barr virus genomes in Hodgkin's disease. Am J Pathol 137: 13–18

    PubMed  Google Scholar 

  28. Honjo T, Walt F, Rabbitts TH (1989) Immunoglobulin genes. Academic, London

    Google Scholar 

  29. Juneja S, Lukeis R, Tan L, Cooper I, Szelag G, Parkin JD, Ironside P, Garson OM (1990) Cytogenetic analysis of 147 cases of non-Hodgkin's lymphoma: non-random chromosomal abnormalities and histological correlations. Br J Haematol 76: 231–237

    PubMed  Google Scholar 

  30. Kaneko Y, Frizzera G, Edarnura S, Maseki N, Sakurai M, Komada Y, Tanaka H, Sasaki M, Suchi T, Kikuta A, Wakasa H, Hojo H, Mizutani S (1989) A novel translocation, t(2;5) (p23;q35), in childhood phagocytic large T-cell lymphoma mimicking malignant histiocytosis. Blood 73: 806–806

    PubMed  Google Scholar 

  31. Klein G, Klein E (1985) Evolution of tumours and the impact of molecular oncology. Nature 315: 190–195

    PubMed  Google Scholar 

  32. Korsmeyer SJ, Arnold A, Bakhshi A, Ravetch JV, Siebenlist U, Hieter PA, Sharrow SO, Lebien TW, Kersey JH, Poplack DG, Leder P (1983) Immunoglobulin gene rearrangement and cell surface antigen expression in acute lymphocytic leukemias of T cell and B cell precursor origins. J Clin Invest 71: 301–313

    PubMed  Google Scholar 

  33. Kramer MHH, Raghoebier S, de Jong D, Willemze R, Kluin PM, Kluin-Nelemans JC (1990) De novo acute B-cell leukemia with translocation t(14;18): an entity with a poor prognosis. Blood 76: 291a

    Google Scholar 

  34. Krawinkel U, Christoph T, Blankenstein T (1989) Organization of the Ig VH locus in mice and humans. Immunol Today 10: 339–344

    PubMed  Google Scholar 

  35. Krawinkel U, Radbruch A (1987) Immunoglobulin heavy chain class switching. In: Calabi F, Neuberger MS (eds) Molecular genetics of immunoglobulin. Elsevier Scientific, Amsterdam, pp 135–151

    Google Scholar 

  36. Krowczynska AM, Rudders RA, Krontiris TG (1990) The human minisatellite consensus at breakpoints of oncogene translocations. Nucleic Acids Res 18: 1121–1127

    PubMed  Google Scholar 

  37. Le Beau MM, Bitter MA, Larson RA, Doane LA, Ellis ED, Franklin WA, Rubin CM, Kadin ME, Vardiman JW (1989) The t(2;5)(p23;q35): a recurring chromosomal abnormality in Ki-1-positive anaplastic large cell lymphoma. Leukemia 3: 866–870

    PubMed  Google Scholar 

  38. Lee M-S, Blick MB, Pathak S, Trujillo JM, Butler JJ, Katz RL, McLaughlin P, Hagemeister FB, Velasquez WS, Goodacre A, Gutterman JU, Cabanillas F (1987) The gene located at chromosome 18 band q21 is rearranged in uncultured diffuse lymphomas as well as follicular lymphomas. Blood 70: 90–95

    PubMed  Google Scholar 

  39. Limpens J, de Jong D, Voetdijk AMH, Price C, Young BD, van Ommen GJB, van Krieken JHJM, Slaper-Cortenbach I, Kluin PM (1990) Translocation t(14;18) in benign lymphocytes. Blood 76: 237a

    Google Scholar 

  40. Matsuzaki H, Hata H, Asou N, Suzushima H, Akahoshi Y, Yoshida M, Nagakura S, Ishii T, Sanada I, Takatsuki K (1990) Establishment and characterization of acute B-cell lymphocytic leukemia cell line showing (8;14) and (14;18) chromosome translocation. Acta Haematol (Basel) 84: 156–161

    Google Scholar 

  41. McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U, McKearn JP, Korsmeyer SJ (1989)bcl-2-Immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 57: 79–88

    PubMed  Google Scholar 

  42. McDonnell TJ, Nunez G, Platt FM, Hockenberry D, London L, McKearn JP, Korsmeyer SJ (1990) Deregulatedbcl-2-immunoglobulin transgene expands a resting but responsive immunoglobulin M and D-expressing B-cell population. Mol Cell Biol 10: 1901–1907

    PubMed  Google Scholar 

  43. Medeiros LJ, van Krieken JH, Jaffe ES, Raffeid M (1990) Association ofbcl-1 rearrangements with lymphocytic lymphoma of intermediate differentiation. Blood 76: 2086–2090

    PubMed  Google Scholar 

  44. Morgan R, Smith SD, Hecht BK, Christy V, Mellentin JD, Warnke R, Cleary ML (1989) Lack of involvement of the c-fms and N-myc genes by chromosomal translocation t(2;5)(p23;q35) common to malignancies with features of so-called malignant histiocytosis. Blood 73: 2155–2164

    PubMed  Google Scholar 

  45. Mufti GJ, Hamblin TJ, Oscier DG, Johnson S (1983) Common ALL with pre-B-cell features showing (8;14) and (14;18) chromosome translocations. Blood 62: 1142–1146

    PubMed  Google Scholar 

  46. Neri A, Barriga F, Knowles DM, Magrath IT, Dalla-Favera R (1988) Different regions of the immunoglobulin heavy-chain locus are involved in chromosomal translocations in distinct pathogenetic forms of Burkitt lymphomas. Proc Natl Acad Sci USA 85: 2748–2752

    PubMed  Google Scholar 

  47. Neuberger MS, Cook GP (1988) The expression of immunoglobulin genes. Immunol Todey 9: 278–281

    Google Scholar 

  48. Nishida K, Taniwaki M, Misawa S, Abe T (1989) Nonrandom rearrangement of chromosome 14 at band q32.33 in human lymphoid malignancies with mature B-cell phenotype. Cancer Res 49: 1275–1281

    PubMed  Google Scholar 

  49. Nowell PC, Croce CM (1990) Philip Levine award lecture: Chromosome translocations and oncogenes in human lymphoid tumors. Am J Clin Pathol 94: 229–237

    PubMed  Google Scholar 

  50. Offit K, Koduru PRK, Hollis R, Filippa D, Jhanwar SC, Clarkson BC, Chaganti RSK (1989) 18q21 rearrangement in diffuse large cell lymphoma: incidence and clinical significance. Br J Haematol 72: 178–183

    PubMed  Google Scholar 

  51. Otter R, Gerrits WBJ, Sandt MMVD, Hermans J, Willemze R (1989) Primary extranodal and nodal non-Hodgkin's lymphoma. A survey of a population-based registry. Eur J Cancer Clin Oncol 25: 1203–1210

    PubMed  Google Scholar 

  52. Pan L, Diss TC, Cunningham D, Isaacson PG (1989) Thebcl-2 gene in primary B cell lymphoma of mucosa-associated lymphoid tissue (MALT). Am J Pathol 135: 7–11

    PubMed  Google Scholar 

  53. Perry DA, Bast MA, Armitage JO, Weisenburger DD (1990) Diffuse intermediate lymphocytic lymphoma: a clinicopathologic study and comparison with small lymphocytic lymphoma and diffuse small cleaved cell lymphoma. Cancer 66: 1995–2000

    PubMed  Google Scholar 

  54. Pezzella F, Ralfkiaer E, Gatter KC, Masons DY (1990) The 14;18 translocation in European cases of follicular lymphoma: comparison of Southern blotting and the polymerase chain reaction. Br J Haematol 76: 58–64

    PubMed  Google Scholar 

  55. Pezzella F, Tse AGD, Cordeil JL, Pulford KAF, Gatter KC, Mason DY (1990) Expression of thebcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation. Am J Pathol 137: 225–232

    PubMed  Google Scholar 

  56. Rabbitts TH, Douglas J, Fischer P, Nacheva E, Karpas A, Catovsky D, Melo JV, Baer R, Stinson MA, Rabbitts PH (1988) Chromosome abnormalities at 11q13 in B cell tumours. Oncogene 3: 99–103

    Google Scholar 

  57. Raghoebier S, Van Krieken JHJM, Kluin-Nelemans JC, Gillis A, van Ommen GJB, Ginsburg AM, Raffeid M, Kluin PM (1991) Oncogene rearrangements in chronic B-cell leukemia. Blood (in press)

  58. Rechavi G, Brok-Simoni F, Katzir N, Mandel M, Umiel T, Stark B, Zaizov R, Ben-Bassat I, Ramot B (1988) More than two immunoglobulin heavy chain J region genes in the majority of infant leukemias. Leukemia 2: 347–350

    PubMed  Google Scholar 

  59. Reth M, Jackson S, Alt FW (1986) VHDJH formation and DJH replacement during pre-B differentiation: non-random usage of gene segments. EMBO J 5: 2131–2138

    PubMed  Google Scholar 

  60. Rimokh R, Magaud J-P, Berger F, Samarut J, Coiffier B, Germain D, Mason DY (1989) A translocation involving a specific breakpoint (q35) on chromosome 5 is characteristic of anaplastic large cell lymphoma (Ki-1 lymphoma). Br J Haematol 71: 31–36

    PubMed  Google Scholar 

  61. Schmidt EV, Pattengale PK, Weir L, Leder P (1988) Transgenic mice bearing the human c-myc gene activated by an immunoglobulin enhancer: a pre-B-cell lymphoma model. Proc Natl Acad Sci USA 85: 6047–6051

    PubMed  Google Scholar 

  62. Siegelman MH, Cleary ML, Warnke R, Sklar J (1985) Frequent biclonality and Ig gene alterations among B cell lymphomas that show multiple histologic forms. J Exp Med 161: 850–863

    PubMed  Google Scholar 

  63. Stern M-H, Lipkowitz S, Aurias A, Griscelli C, Thomas G, Kirsch IR (1989) Inversion of chromosome 7 in ataxia telangiectasia is generated by a rearrangement between T-cell receptor β and T-cell receptor gamma genes. Blood 74: 2076–2080

    PubMed  Google Scholar 

  64. Taussig MJ, Sims MJ, Krawinkel U (1989) Regulation of immunoglobulin gene rearrangement and expression. Immunol Today 10: 143–146

    PubMed  Google Scholar 

  65. Thangavelu M, Olopade O, Beckman E, Vardiman JW, Larson RA, McKeithan TW, LeBeau MM, Rowley JD (1990) Clinical, morphologic, and cytogenetic characteristics of patients with lymphoid malignancies characterized by both t(14;18)(q32;q21) and t(8;14)(q24;q32) or t(8;22)(q24;q11). Gen Chrom Canc 2: 147–158

    Google Scholar 

  66. Tsujimoto Y (1989) Stress-resistance conferred by high level of bcl-2α protein in human B lymphoblastoid cell. Oncogene 4: 1331–1336

    PubMed  Google Scholar 

  67. Tsujimoto Y, Bashir MM, Givol I, Cossman J, Jaffe E, Croce CM (1987) DNA rearrangements in human follicular lymphoma can involve the 5′ or the 3′ region of thebcl-2 gene. Proc Natl Acad Sci USA 84: 1329–1331

    PubMed  Google Scholar 

  68. Tsujimoto Y, Gorham J, Cossman J, Jaffe E, Croce CM (1985) The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science 229: 1390–1393

    PubMed  Google Scholar 

  69. Tsujimoto Y, Louie E, Bashir MM, Croce CM (1988) The reciprocal partners of both the t(14;18) and the t(11;14) translocations involved in B-cell neoplasms are rearranged by the same mechanism. Oncogene 2: 347–351

    PubMed  Google Scholar 

  70. Tsujimoto Y, Yunis JJ, Onorato-Showe L, Erikson J, Nowell PC, Croce CM (1984) Molecular cloning of the chromosomal breakpoint of B-cell lymphomas and leukemias with the t(ll;14) chromosome translocation. Science 224: 1403–1406

    PubMed  Google Scholar 

  71. Tycko B, Palmer JD, Sklar J (1989) T-cell receptor gene transrearrangements: chimeric gamma-delta genes in normal lymphoid tissues. Science 245: 1242–1246

    PubMed  Google Scholar 

  72. Van der Harst D, de Jong D, Limpens J, Kluin PM, Rozier Y, van Ommen GJB, Brand A (1990) Clonal B-cell populations in patients with idiopathic thrombocytopenic purpura. Blood 76: 2321–2326

    PubMed  Google Scholar 

  73. Van Krieken JHJM, Otter R, Hermans J, van Groningen K, Spaander PJ, van de Sandt MM, Keuning JF, Kluin PM (1989) Malignant lymphoma of the gastrointestinal tract and mesentery: a clinico-pathologic study of the significance of histologic classification. Am J Pathol 135: 281–289

    PubMed  Google Scholar 

  74. Van Krieken JHJM, Raffeld M, Raghoebier S, Jaffe ES, van Ommen GJB, Kluin PM (1990) Molecular genetics of gastrointestinal non-Hodgkin's lymphomas: unusual prevalence and pattern of c-myc rearrangements in aggressive lymphomas. Blood 76: 797–800

    PubMed  Google Scholar 

  75. Van den Berghe H, Vermaelen K, Louwagie A, Criel A, Mecucci C, Vaerman J-P (1984) High incidence of chromosome abnormalities in IgG3 myeloma. Cancer Genet Cytogenet 11: 381–387

    PubMed  Google Scholar 

  76. Weisenburger DD, Sanger WG, Armitage JO, Purtilo DT (1987) Intermediate lymphocytic lymphoma: immunophenotypic and cytogenetic findings. Blood 69: 1617–1621

    Google Scholar 

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

    PubMed  Google Scholar 

  78. Williams ME, Westermann CD, Swerdlow SH (1990) Genotypic characterization of centrocytic lymphoma: frequent rearrangement of the chromosome 11bcl-1 locus. Blood 76: 1387–1391

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  80. Yunis JJ, Mayer MG, Arnesen MA, Aeppli DP, Oken MM, Frizzera G (1989)bcl-2 and other genomic alterations in the prognosis of large-cell lymphoma. N Engl J Med 320: 1047–1054

    PubMed  Google Scholar 

  81. Yunis JJ, Oken MM, Kaplan ME, Ensrud KM, Howe RR, Theologides A (1982) Distinctive chromosomal abnormalities in histologic subtypes of non-Hodgkin's lymphomas. N Engl J Med 307: 1231–1236

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

Supported by the Netherlands Cancer Foundation NKB-KWF

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kluin, P.M., van Krieken, J.H.J.M. The molecular biology of B-cell lymphoma: Clinicopathologic implications. Ann Hematol 62, 95–102 (1991). https://doi.org/10.1007/BF01702921

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01702921

Key words

Navigation