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Decision making in the immune system

Lymphoid Malignancies: the dark side of B-cell differentiation

Nature Reviews Immunology volume 2, pages 920–933 (2002)Cite this article

Key Points

  • Mature B-cell malignancies are initiated often by errors in immunoglobulin gene variable–diversity–joining region (VDJ) recombination, somatic hypermutation and/or class-switch recombination that lead to chromosomal translocations. Dysregulation of the genes at the translocation breakpoints disrupts B-cell homeostasis by perturbing proliferation, apoptosis and differentiation.

  • Advances in molecular analyses, in particular gene-expression profiling, have increased the precision of diagnosis for lymphoid malignancies. These methods have shown that lymphomas and leukaemias can share gene-expression programmes with their normal cellular counterparts. Molecular profiling has shown that some of the diagnostic categories that are used at present consist of many molecularly distinct diseases that cannot be distinguished morphologically.

  • Antigenic stimulation and selection have crucial roles in the pathogenesis and persistence of some lymphomas and leukaemias. The identification and elimination of an antigenic stimulus can eradicate some tumours.

  • Improved molecular classification and an understanding of the pathogenetic mechanisms that are involved in lymphoid malignancies are providing new molecular targets for therapy.

Abstract

When the regulation of B-cell differentiation and activation is disrupted, lymphomas and leukaemias can occur. The processes that normally create immunoglobulin diversity might be misdirected, resulting in oncogenic chromosomal translocations that block differentiation, prevent apoptosis and/or promote proliferation. Prolonged or unregulated antigenic stimulation might contribute further to the development and progression of some malignancies. Lymphoid malignancies often resemble normal stages of B-cell differentiation, as shown by molecular techniques such as gene-expression profiling. The similarities and differences between malignant and normal B cells indicate strategies for the treatment of these cancers.

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Figure 1: Mature B-cell lymphomas: cell of origin.
Figure 2: Mechanisms of malignant transformation of germinal-centre B cells.
Figure 3: The relationship between B-cell differentiation and lymphomagenesis.
Figure 4: Chronic lymphocytic leukaemia: a disease of antigen-experienced B cells.

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References

  1. Fugmann, S. D., Lee, A. I., Shockett, P. E., Villey, I. J. & Schatz, D. G. The RAG proteins and V(D)J recombination: complexes, ends and transposition. Annu. Rev. Immunol. 18, 495–527 (2000).

    CAS  PubMed  Google Scholar 

  2. Marculescu, R., Le, T., Simon, P., Jaeger, U. & Nadel, B. V(D)J-mediated translocations in lymphoid neoplasms: a functional assessment of genomic instability by cryptic sites. J. Exp. Med. 195, 85–98 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Boehm, T. et al. Alternating purine–pyrimidine tracts may promote chromosomal translocations seen in a variety of human lymphoid tumours. EMBO J. 8, 2621–2631 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Welzel, N. et al. Templated nucleotide addition and immunoglobulin JH-gene utilization in t(11;14) junctions: implications for the mechanism of translocation and the origin of mantle-cell lymphoma. Cancer Res. 61, 1629–1636 (2001).

    CAS  PubMed  Google Scholar 

  5. Yu, W. et al. Continued RAG expression in late stages of B-cell development and no apparent re-induction after immunization. Nature 400, 682–687 (1999).

    CAS  PubMed  Google Scholar 

  6. Gartner, F., Alt, F. W., Monroe, R. J. & Seidl, K. J. Antigen-independent appearance of recombination activating gene (RAG)-positive bone-marrow B cells in the spleens of immunized mice. J. Exp. Med. 192, 1745–1754 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. MacLennan, I. C. Germinal centers. Annu. Rev. Immunol. 12, 117–139 (1994).

    CAS  PubMed  Google Scholar 

  8. Liu, Y. J., Zhang, J., Lane, P. J., Chan, E. Y. & MacLennan, I. C. Sites of specific B-cell activation in primary and secondary responses to T-cell-dependent and T-cell-independent antigens. Eur. J. Immunol. 21, 2951–2962 (1991).

    CAS  PubMed  Google Scholar 

  9. Chua, K. F., Alt, F. W. & Manis, J. P. The function of AID in somatic mutation and class-switch recombination: upstream or downstream of DNA breaks. J. Exp. Med. 195, F37–F41 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Honjo, T., Kinoshita, K. & Muramatsu, M. Molecular mechanism of class-switch recombination: linkage with somatic hypermutation. Annu. Rev. Immunol. 20, 165–196 (2002).

    CAS  PubMed  Google Scholar 

  11. Papavasiliou, F. N. & Schatz, D. G. Somatic hypermutation of immunoglobulin genes: merging mechanisms for genetic diversity. Cell 109, S35–S44 (2002).

    CAS  PubMed  Google Scholar 

  12. Pelicci, P. G., Knowles, D. M. 2nd, Magrath, I. & Dalla-Favera, R. Chromosomal breakpoints and structural alterations of the c-myc locus differ in endemic and sporadic forms of Burkitt lymphoma. Proc. Natl Acad. Sci. USA 83, 2984–2988 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Rabbitts, T. H., Hamlyn, P. H. & Baer, R. Altered nucleotide sequences of a translocated c-myc gene in Burkitt lymphoma. Nature 306, 760–765 (1983).

    CAS  PubMed  Google Scholar 

  14. Goossens, T., Klein, U. & Kuppers, R. Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy-chain disease. Proc. Natl Acad. Sci. USA 95, 2463–2468 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Pasqualucci, L. et al. BCL-6 mutations in normal germinal-center B cells: evidence of somatic hypermutation acting outside Ig loci. Proc. Natl Acad. Sci. USA 95, 11816–11821 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Shen, H. M., Peters, A., Baron, B., Zhu, X. & Storb, U. Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 280, 1750–1752 (1998).

    CAS  PubMed  Google Scholar 

  17. Pasqualucci, L. et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412, 341–346 (2001). This study shows that diffuse large B-cell lymphomas (DLBCLs) can accumulate mutations in non-immunoglobulin genes as a result of somatic hypermutation (SHM).

    CAS  PubMed  Google Scholar 

  18. Neri, A., Barriga, F., Knowles, D. M., Magrath, I. T. & Dalla-Favera, R. Different regions of the immunoglobulin heavy-chain locus are involved in chromosomal translocations in distinct pathogenetic forms of Burkitt lymphoma. Proc. Natl Acad. Sci. USA 85, 2748–2752 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Bergsagel, P. L. et al. Promiscuous translocations into immunoglobulin heavy-chain switch regions in multiple myeloma. Proc. Natl Acad. Sci. USA 93, 13931–13936 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Jacob, J., Kelsoe, G., Rajewsky, K. & Weiss, U. Intraclonal generation of antibody mutants in germinal centers. Nature 354, 389–392 (1991).

    CAS  PubMed  Google Scholar 

  21. Han, S. et al. Cellular interaction in germinal centers. Roles of CD40 ligand and B7-2 in established germinal centers. J. Immunol. 155, 556–567 (1995).

    CAS  PubMed  Google Scholar 

  22. Kawabe, T. et al. The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1, 167–178 (1994).

    CAS  PubMed  Google Scholar 

  23. Weller, S. et al. CD40–CD40L-independent Ig gene hypermutation suggests a second B-cell diversification pathway in humans. Proc. Natl Acad. Sci. USA 98, 1166–1170 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Matsumoto, M. et al. Affinity maturation without germinal centres in lymphotoxin-α-deficient mice. Nature 382, 462–466 (1996).

    CAS  PubMed  Google Scholar 

  25. William, J., Euler, C., Christensen, S. & Shlomchik, M. J. Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science 297, 2066–2070 (2002). References 23–25 provide evidence for SHM in the absence of recognizable germinal centres (GCs).

    CAS  PubMed  Google Scholar 

  26. Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene-expression profiling. Nature 403, 503–511 (2000).

    CAS  PubMed  Google Scholar 

  27. Shaffer, A. L. et al. Signatures of the immune response. Immunity 15, 375–385 (2001).

    CAS  PubMed  Google Scholar 

  28. Alizadeh, A. et al. The Lymphochip: a specialized cDNA microarray for the genomic-scale analysis of gene expression in normal and malignant lymphocytes. Cold Spring Harb. Symp. Quant. Biol. 64, 71–78 (1999).

    CAS  PubMed  Google Scholar 

  29. Rosenwald, A. et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N. Engl. J. Med. 346, 1937–1947 (2002). References 26 and 29 show the utility of gene-expression profiling for the analysis of human B-cell lymphomas, and show that a single diagnostic category (DLBCL) is composed of many molecularly distinct diseases with different clinical outcomes.

    PubMed  Google Scholar 

  30. Lossos, I. S. et al. Ongoing immunoglobulin somatic mutation in germinal center B-cell-like, but not in activated B-cell-like, diffuse large-cell lymphomas. Proc. Natl Acad. Sci. USA 97, 10209–10213 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Davis, R. E., Brown, K. D., Siebenlist, U. & Staudt, L. M. Constitutive nuclear factor-κB activity is required for survival of activated B-cell-like diffuse large B-cell lymphoma cells. J. Exp. Med. 194, 1861–1874 (2001). This work shows that the NF-κB pathway is constitutively active in activated B-cell-like DLBCLs, and that it is a potential therapeutic target.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Angelin-Duclos, C., Cattoretti, G., Lin, K. I. & Calame, K. Commitment of B lymphocytes to a plasma-cell fate is associated with Blimp-1 expression in vivo. J. Immunol. 165, 5462–5471 (2000).

    CAS  PubMed  Google Scholar 

  33. Falini, B. et al. A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4 protein in a subset of germinal-center B cells, plasma cells and activated T cells. Blood 95, 2084–2092 (2000).

    CAS  PubMed  Google Scholar 

  34. Levens, D. Disentangling the MYC web. Proc. Natl Acad. Sci. USA 99, 5757–5759 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Martinez-Valdez, H. et al. Human germinal-center B cells express the apoptosis-inducing genes Fas, c-Myc, P53 and Bax, but not the survival gene Bcl-2. J. Exp. Med. 183, 971–977 (1996).

    CAS  PubMed  Google Scholar 

  36. Cutrona, G. et al. The propensity to apoptosis of centrocytes and centroblasts correlates with elevated levels of intracellular myc protein. Eur. J. Immunol. 27, 234–238 (1997).

    CAS  PubMed  Google Scholar 

  37. Dalla-Favera, R., Martinotti, S., Gallo, R. C., Erikson, J. & Croce, C. M. Translocation and rearrangements of the c-myc oncogene locus in human undifferentiated B-cell lymphomas. Science 219, 963–967 (1983).

    CAS  PubMed  Google Scholar 

  38. Akasaka, T. et al. Molecular and clinical features of non-Burkitt's, diffuse large-cell lymphoma of B-cell type associated with the c-MYC/immunoglobulin heavy-chain fusion gene. J. Clin. Oncol. 18, 510–518 (2000).

    CAS  PubMed  Google Scholar 

  39. Hoang, A. T. et al. A link between increased transforming activity of lymphoma-derived MYC mutant alleles, their defective regulation by p107 and altered phosphorylation of the c-Myc transactivation domain. Mol. Cell. Biol. 15, 4031–4042 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu, Y. J. et al. Germinal-center cells express bcl-2 protein after activation by signals which prevent their entry into apoptosis. Eur. J. Immunol. 21, 1905–1910 (1991).

    CAS  PubMed  Google Scholar 

  41. Pezzella, F. et al. Expression of the bcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation. Am. J. Pathol. 137, 225–232 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Craxton, A., Chuang, P. I., Shu, G., Harlan, J. M. & Clark, E. A. The CD40-inducible Bcl-2 family member A1 protects B cells from antigen receptor-mediated apoptosis. Cell. Immunol. 200, 56–62 (2000).

    CAS  PubMed  Google Scholar 

  43. Karin, M. & Lin, A. NF-κB at the crossroads of life and death. Nature Immunol. 3, 221–227 (2002).

    CAS  Google Scholar 

  44. Hinz, M. et al. Constitutive NF-κB maintains high expression of a characteristic gene network, including CD40, CD86 and a set of antiapoptotic genes in Hodgkin/Reed-Sternberg cells. Blood 97, 2798–2807 (2001).

    CAS  PubMed  Google Scholar 

  45. Pahl, H. L. Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18, 6853–6866 (1999).

    CAS  PubMed  Google Scholar 

  46. Tuscano, J. M. et al. Bcl-X rather than Bcl-2 mediates CD40-dependent centrocyte survival in the germinal center. Blood 88, 1359–1364 (1996).

    CAS  PubMed  Google Scholar 

  47. Bakhshi, A. et al. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 41, 899–906 (1985).

    CAS  PubMed  Google Scholar 

  48. Tsujimoto, Y., Cossman, J., Jaffe, E. & Croce, C. M. Involvement of the bcl-2 gene in human follicular lymphoma. Science 228, 1440–1443 (1985).

    CAS  PubMed  Google Scholar 

  49. Monni, O. et al. BCL2 overexpression associated with chromosomal amplification in diffuse large B-cell lymphoma. Blood 90, 1168–1174 (1997).

    CAS  PubMed  Google Scholar 

  50. Neri, A. et al. Molecular analysis of cutaneous B- and T-cell lymphomas. Blood 86, 3160–3172 (1995).

    CAS  PubMed  Google Scholar 

  51. Cabannes, E., Khan, G., Aillet, F., Jarrett, R. F. & Hay, R. T. Mutations in the IkBa gene in Hodgkin's disease suggest a tumour suppressor role for IκBα. Oncogene 18, 3063–3070 (1999).

    CAS  PubMed  Google Scholar 

  52. Jungnickel, B. et al. Clonal deleterious mutations in the IκBα gene in the malignant cells in Hodgkin's lymphoma. J. Exp. Med. 191, 395–402 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Akagi, T. et al. A novel gene, MALT1 at 18q21, is involved in t(11;18) (q21;q21) found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue. Oncogene 18, 5785–5794 (1999).

    CAS  PubMed  Google Scholar 

  54. Lucas, P. C. et al. Bcl10 and MALT1, independent targets of chromosomal translocation in MALT lymphoma, cooperate in a novel NF-κB signaling pathway. J. Biol. Chem. 276, 19012–19019 (2001).

    CAS  PubMed  Google Scholar 

  55. Uren, A. G. et al. Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma. Mol. Cell. 6, 961–967 (2000).

    CAS  PubMed  Google Scholar 

  56. Zhang, Q. et al. Inactivating mutations and overexpression of BCL10, a caspase recruitment domain-containing gene, in MALT lymphoma with t(1;14)(p22;q32). Nature Genet. 22, 63–68 (1999).

    CAS  PubMed  Google Scholar 

  57. Ruland, J. et al. Bcl10 is a positive regulator of antigen receptor-induced activation of NF-κB and neural-tube closure. Cell 104, 33–42 (2001).

    CAS  PubMed  Google Scholar 

  58. Sylla, B. S. et al. Epstein–Barr virus-transforming protein latent infection membrane protein 1 activates transcription factor NF-κB through a pathway that includes the NF-κB-inducing kinase and the IκB kinases IKKα and IKKβ. Proc. Natl Acad. Sci. USA 95, 10106–10111 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Krappmann, D. et al. Molecular mechanisms of constitutive NF-κB/Rel activation in Hodgkin/Reed-Sternberg cells. Oncogene 18, 943–953 (1999).

    CAS  PubMed  Google Scholar 

  60. Staudt, L. M., Dent, A. L., Shaffer, A. L. & Yu, X. Regulation of lymphocyte cell-fate decisions and lymphomagenesis by BCL-6. Int. Rev. Immunol. 18, 381–403 (1999).

    CAS  PubMed  Google Scholar 

  61. Dalla-Favera, R. et al. Molecular pathogenesis of B-cell malignancy: the role of BCL-6. Curr. Top. Microbiol. Immunol. 246, 257–263 (1999).

    CAS  PubMed  Google Scholar 

  62. Allman, D. et al. BCL-6 expression during B-cell activation. Blood 87, 5257–5268 (1996).

    CAS  PubMed  Google Scholar 

  63. Cattoretti, G. et al. Bcl-6 protein is expressed in germinal-center B cells. Blood 86, 45–53 (1995).

    CAS  PubMed  Google Scholar 

  64. Dent, A. L., Shaffer, A. L., Yu, X., Allman, D. & Staudt, L. M. Control of inflammation, cytokine expression and germinal-center formation by BCL-6. Science 276, 589–592 (1997).

    CAS  PubMed  Google Scholar 

  65. Ye, B. H. et al. The BCL-6 proto-oncogene controls germinal-centre formation and TH2-type inflammation. Nature Genet. 16, 161–170 (1997).

    CAS  PubMed  Google Scholar 

  66. Fukuda, T. et al. Disruption of the Bcl6 gene results in an impaired germinal-center formation. J. Exp. Med. 186, 439–448 (1997). References 64–66 use Bcl-6-deficient mice to show that Bcl-6 is required for GC formation and that it regulates inflammation.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Shaffer, A. L. et al. BCL-6 represses genes that function in lymphocyte differentiation, inflammation and cell-cycle control. Immunity 13, 199–212 (2000).

    CAS  PubMed  Google Scholar 

  68. Reljic, R., Wagner, S. D., Peakman, L. J. & Fearon, D. T. Suppression of signal transducer and activator of transcription 3-dependent B-lymphocyte terminal differentiation by BCL-6. J. Exp. Med. 192, 1841–1848 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Vasanwala, F. H., Kusam, S., Toney, L. M. & Dent, A. L. Repression of AP-1 function: a mechanism for the regulation of Blimp-1 expression and B-lymphocyte differentiation by the B-cell lymphoma-6 protooncogene. J. Immunol. 169, 1922–1929 (2002). References 67–69 identify genes that are inhibited by BCL-6 in B cells, including genes that control the cell cycle ( p27KIP1 ) and differentiation ( BLIMP1).

    CAS  PubMed  Google Scholar 

  70. Turner, C. A. Jr, Mack, D. H. & Davis, M. M. Blimp-1, a novel zinc-finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell 77, 297–306 (1994).

    CAS  PubMed  Google Scholar 

  71. Shaffer, A. L. et al. Blimp-1 orchestrates plasma-cell differentiation by extinguishing the mature B-cell gene-expression program. Immunity 17, 51–62 (2002). This study shows that BLIMP1 acts as the master regulator of plasma-cell differentiation by extinguishing gene-expression programmes that direct proliferation and GC B-cell functions, such as class-switch recombination. BLIMP1 mediates these broad effects by regulating the expression of other transcription factors directly and by reciprocally repressing BCL6.

    CAS  PubMed  Google Scholar 

  72. Lin, Y., Wong, K. & Calame, K. Repression of c-myc transcription by Blimp-1, an inducer of terminal B-cell differentiation. Science 276, 596–599 (1997).

    CAS  PubMed  Google Scholar 

  73. Niu, H., Ye, B. H. & Dalla-Favera, R. Antigen-receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev. 12, 1953–1961 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Shvarts, A. et al. A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19(ARF)–p53 signaling. Genes Dev. 16, 681–686 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Alexander, K. & Hinds, P. W. Requirement for p27(KIP1) in retinoblastoma protein-mediated senescence. Mol. Cell. Biol. 21, 3616–3631 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Iida, S. et al. The t(9;14)(p13;q32) chromosomal translocation associated with lymphoplasmacytoid lymphoma involves the PAX-5 gene. Blood 88, 4110–4117 (1996).

    CAS  PubMed  Google Scholar 

  77. Urbanek, P., Wang, Z. Q., Fetka, I., Wagner, E. F. & Busslinger, M. Complete block of early B-cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5/BSAP. Cell 79, 901–912 (1994).

    CAS  PubMed  Google Scholar 

  78. Nutt, S. L., Heavey, B., Rolink, A. G. & Busslinger, M. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature 401, 556–562 (1999).

    CAS  PubMed  Google Scholar 

  79. Mikkola, I., Heavey, B., Horcher, M. & Busslinger, M. Reversion of B-cell commitment upon loss of Pax5 expression. Science 297, 110–113 (2002).

    CAS  PubMed  Google Scholar 

  80. Horcher, M., Souabni, A. & Busslinger, M. Pax5/BSAP maintains the identity of B cells in late B lymphopoiesis. Immunity 14, 779–790 (2001). References 77–80 delineate the essential role of PAX5 in committing cells to and maintaining them in the B-cell lineage.

    CAS  PubMed  Google Scholar 

  81. Reimold, A. M. et al. Transcription factor B-cell lineage-specific activator protein regulates the gene for human X-box binding protein 1. J. Exp. Med. 183, 393–401 (1996).

    CAS  PubMed  Google Scholar 

  82. Reimold, A. M. et al. Plasma-cell differentiation requires the transcription factor XBP-1. Nature 412, 300–307 (2001).

    CAS  PubMed  Google Scholar 

  83. Lin, K. I., Angelin-Duclos, C., Kuo, T. C. & Calame, K. Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin-M-secreting plasma cells. Mol. Cell. Biol. 22, 4771–4780 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Vaandrager, J. W. et al. DNA fiber fluorescence in situ hybridization analysis of immunoglobulin class switching in B-cell neoplasia: aberrant CH gene rearrangements in follicle center-cell lymphoma. Blood 92, 2871–2878 (1998).

    CAS  PubMed  Google Scholar 

  85. Lam, K. P., Kuhn, R. & Rajewsky, K. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90, 1073–1083 (1997).

    CAS  PubMed  Google Scholar 

  86. Cavalli, F., Isaacson, P. G., Gascoyne, R. D. & Zucca, E. MALT lymphomas. Hematology (Am. Soc. Hematol. Educ. Program) 241–258 (2001).

  87. Wotherspoon, A. C. et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 342, 575–577 (1993).

    CAS  PubMed  Google Scholar 

  88. Bayerdorffer, E. et al. Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. MALT Lymphoma Study Group. Lancet 345, 1591–1594 (1995).

    CAS  PubMed  Google Scholar 

  89. Morgner, A. et al. Complete remission of primary high-grade B-cell gastric lymphoma after cure of Helicobacter pylori infection. J. Clin. Oncol. 19, 2041–2048 (2001).

    CAS  PubMed  Google Scholar 

  90. Hussell, T., Isaacson, P. G., Crabtree, J. E. & Spencer, J. The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori. Lancet 342, 571–574 (1993).

    CAS  PubMed  Google Scholar 

  91. Qin, Y. et al. Somatic hypermutation in low-grade mucosa-associated lymphoid tissue-type B-cell lymphoma. Blood 86, 3528–3534 (1995).

    CAS  PubMed  Google Scholar 

  92. Du, M. et al. Ongoing mutation in MALT lymphoma immunoglobulin gene suggests that antigen stimulation plays a role in the clonal expansion. Leukemia 10, 1190–1197 (1996).

    CAS  PubMed  Google Scholar 

  93. Zuckerman, E. et al. Hepatitis C virus infection in patients with B-cell non-Hodgkin lymphoma. Ann. Intern. Med. 127, 423–428 (1997).

    CAS  PubMed  Google Scholar 

  94. Rabkin, C. S. et al. Prospective study of hepatitis C viral infection as a risk factor for subsequent B-cell neoplasia. Blood 99, 4240–4242 (2002).

    CAS  PubMed  Google Scholar 

  95. Hermine, O. et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N. Engl. J. Med. 347, 89–94 (2002).

    CAS  PubMed  Google Scholar 

  96. Quinn, E. R. et al. The B-cell receptor of a hepatitis C virus (HCV)-associated non-Hodgkin lymphoma binds the viral E2 envelope protein, implicating HCV in lymphomagenesis. Blood 98, 3745–3749 (2001).

    CAS  PubMed  Google Scholar 

  97. Jaffe, E. S., Harris, N. L., Stein, H., Vardiman, J. W. Tumours of Haematopoietic and Lymphoid Tissues (IARC, Lyon, 2001).

    Google Scholar 

  98. Klein, U. et al. Gene-expression profiling of B-cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J. Exp. Med. 194, 1625–1638 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Rosenwald, A. et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B-cell chronic lymphocytic leukemia. J. Exp. Med. 194, 1639–1648 (2001). References 98 and 99 use gene-expression profiling to show that chronic lymphocytic leukaemia (CLL) is a single disease with at least two variants.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Damle, R. N. et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94, 1840–1847 (1999).

    CAS  PubMed  Google Scholar 

  101. Fais, F. et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J. Clin. Invest. 102, 1515–1525 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Hamblin, T. J., Davis, Z., Gardiner, A., Oscier, D. G. & Stevenson, F. K. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94, 1848–1854 (1999). References 100–102 define two forms of CLL on the basis of the mutational status of immunoglobulin sequences in the leukaemic cells.

    CAS  PubMed  Google Scholar 

  103. Oscier, D. G., Thompsett, A., Zhu, D. & Stevenson, F. K. Differential rates of somatic hypermutation in V(H) genes among subsets of chronic lymphocytic leukemia defined by chromosomal abnormalities. Blood 89, 4153–4160 (1997).

    CAS  PubMed  Google Scholar 

  104. Rawstron, A. C. et al. Monoclonal B lymphocytes with the characteristics of 'indolent' chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood 100, 635–639 (2002).

    CAS  PubMed  Google Scholar 

  105. Tobin, G. et al. Somatically mutated Ig V(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia. Blood 99, 2262–2264 (2002).

    CAS  PubMed  Google Scholar 

  106. Sthoeger, Z. M. et al. Production of autoantibodies by CD5-expressing B lymphocytes from patients with chronic lymphocytic leukemia. J. Exp. Med. 169, 255–268 (1989).

    CAS  PubMed  Google Scholar 

  107. Borche, L., Lim, A., Binet, J. L. & Dighiero, G. Evidence that chronic lymphocytic leukemia B lymphocytes are frequently committed to production of natural autoantibodies. Blood 76, 562–569 (1990).

    CAS  PubMed  Google Scholar 

  108. Kipps, T. J. et al. Developmentally restricted immunoglobulin heavy-chain variable region gene expressed at high frequency in chronic lymphocytic leukemia. Proc. Natl Acad. Sci. USA 86, 5913–5917 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. He, X., Goronzy, J. J., Zhong, W., Xie, C. & Weyand, C. M. VH3-21 B cells escape from a state of tolerance in rheumatoid arthritis and secrete rheumatoid factor. Mol. Med. 1, 768–780 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Caligaris-Cappio, F. B-chronic lymphocytic leukemia: a malignancy of anti-self B cells. Blood 87, 2615–2620 (1996).

    CAS  PubMed  Google Scholar 

  111. Goodnow, C. C. et al. Self-tolerance checkpoints in B-lymphocyte development. Adv. Immunol. 59, 279–368 (1995).

    CAS  PubMed  Google Scholar 

  112. Bell, S. E. & Goodnow, C. C. A selective defect in IgM antigen-receptor synthesis and transport causes loss of cell-surface IgM expression on tolerant B lymphocytes. EMBO J. 13, 816–826 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Payelle-Brogard, B., Magnac, C., Alcover, A., Roux, P. & Dighiero, G. Defective assembly of the B-cell receptor chains accounts for its low expression in B-chronic lymphocytic leukaemia. Br. J. Haematol. 118, 976–985 (2002).

    CAS  PubMed  Google Scholar 

  114. Michel, F. et al. Defective calcium response in B-chronic lymphocytic leukemia cells. Alteration of early protein tyrosine phosphorylation and of the mechanism responsible for cell calcium influx. J. Immunol. 150, 3624–3633 (1993).

    CAS  PubMed  Google Scholar 

  115. Zupo, S. et al. CD38 expression distinguishes two groups of B-cell chronic lymphocytic leukemias with different responses to anti-IgM antibodies and propensity to apoptosis. Blood 88, 1365–1374 (1996).

    CAS  PubMed  Google Scholar 

  116. Lankester, A. C. et al. Antigen-receptor nonresponsiveness in chronic lymphocytic leukemia B cells. Blood 86, 1090–1097 (1995).

    CAS  PubMed  Google Scholar 

  117. Healy, J. I. et al. Different nuclear signals are activated by the B-cell receptor during positive versus negative signaling. Immunity 6, 419–428 (1997).

    CAS  PubMed  Google Scholar 

  118. Vilen, B. J., Burke, K. M., Sleater, M. & Cambier, J. C. Transmodulation of BCR signaling by transduction-incompetent antigen receptors: implications for impaired signaling in anergic B cells. J. Immunol. 168, 4344–4351 (2002).

    CAS  PubMed  Google Scholar 

  119. Schuh, K., Avots, A., Tony, H. P., Serfling, E. & Kneitz, C. Nuclear NF-ATp is a hallmark of unstimulated B cells from B-CLL patients. Leuk. Lymphoma 23, 583–592 (1996).

    CAS  PubMed  Google Scholar 

  120. Krober, A. et al. V(H) mutation status, CD38 expression level, genomic aberrations and survival in chronic lymphocytic leukemia. Blood 100, 1410–1416 (2002).

    CAS  PubMed  Google Scholar 

  121. Adams, J. Preclinical and clinical evaluation of proteasome inhibitor PS-341 for the treatment of cancer. Curr. Opin. Chem. Biol. 6, 493–500 (2002).

    CAS  PubMed  Google Scholar 

  122. Letai, A. et al. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2, 183 (2002).

    CAS  PubMed  Google Scholar 

  123. Mellemkjaer, L. et al. Rheumatoid arthritis and cancer risk. Eur. J. Cancer 32A, 1753–1757 (1996).

    CAS  PubMed  Google Scholar 

  124. Coiffier, B. Diffuse large-cell lymphoma. Curr. Opin. Oncol. 13, 325–334 (2001).

    CAS  PubMed  Google Scholar 

  125. Huang, J. Z. et al. The t(14;18) defines a unique subset of diffuse large B-cell lymphoma with a germinal center B-cell gene-expression profile. Blood 99, 2285–2290 (2002).

    CAS  PubMed  Google Scholar 

  126. Baldwin, A. S. Control of oncogenesis and cancer-therapy resistance by the transcription factor NF-κB. J. Clin. Invest. 107, 241–246 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Shipp, M. A. et al. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nature Med. 8, 68–74 (2002).

    CAS  PubMed  Google Scholar 

  128. Hagman, J. et al. Pax-5/BSAP: regulator of specific gene expression and differentiation in B lymphocytes. Curr. Top. Microbiol. Immunol. 245, 169–194 (2000).

    CAS  PubMed  Google Scholar 

  129. Usui, T. et al. Overexpression of B-cell-specific activator protein (BSAP/Pax-5) in a late B cell is sufficient to suppress differentiation to an Ighigh producer cell with plasma-cell phenotype. J. Immunol. 158, 3197–3204 (1997).

    CAS  PubMed  Google Scholar 

  130. Rosenwald, A. & Staudt, L. M. Clinical translation of gene-expression profiling in lymphomas and leukemias. Semin. Oncol. 29, 258–263 (2002).

    PubMed  Google Scholar 

  131. Thorselius, M. et al. Somatic hypermutation and V(H) gene usage in mantle-cell lymphoma. Eur. J. Haematol. 68, 217–224 (2002).

    CAS  PubMed  Google Scholar 

  132. Algara, P. et al. Analysis of the IgV(H) somatic mutations in splenic marginal-zone lymphoma defines a group of unmutated cases with frequent 7q deletion and adverse clinical course. Blood 99, 1299–1304 (2002).

    CAS  PubMed  Google Scholar 

  133. Thiede, C. et al. Ongoing somatic mutations and clonal expansions after cure of Helicobacter pylori infection in gastric mucosa-associated lymphoid tissue B-cell lymphoma. J. Clin. Oncol. 16, 3822–3831 (1998).

    CAS  PubMed  Google Scholar 

  134. Gurrieri, C. et al. Chronic lymphocytic leukemia B cells can undergo somatic hypermutation and intraclonal immunoglobulin V(H)DJ(H) gene diversification. J. Exp. Med. 196, 629–639 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We wish to thank the members of the Staudt lab and the Lymphoma/Leukemia Molecular Profiling Project for discussions and support.

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Authors and Affiliations

  1. Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    A. L. Shaffer, Andreas Rosenwald & Louis M. Staudt

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  1. A. L. Shaffer
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  2. Andreas Rosenwald
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  3. Louis M. Staudt
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Correspondence to Louis M. Staudt.

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DATABASES

Cancer.gov

Hodgkin lymphoma

leukaemia

lymphoma

Entrez

EBV

LMP1

LocusLink

BAK

BAX

BCL2

BCL6

BCL10

BCL-XL

BLIMP1

BUB1

CD5

CD10

CD40

CD40L

CD44

CD77 synthase

CDC2

c-MAF

c-MYC

c-REL

cyclin D1

cyclin D2

cyclin D3

FGFR3

FLIP

FOXP1

IFN-α

IκBα

IRF4

JAW1

lymphotoxin-α

MALT1

NFATP

NFκB2

p27KIP1

PAX5

PIM1

PLK

RAG1

RAG2

XBP1

Swiss-Prot

BH3 domain

FURTHER INFORMATION

Lymphoma/Leukemia Molecular Profiling Project

Glossary

V(D)J RECOMBINATION

The somatic rearrangement of variable (V), diversity (D) and joining (J) regions of antigen-receptor genes, which leads to the repertoire diversity of both T- and B-cell receptors.

GERMINAL CENTRE

The structure that is formed by the clonal expansion of antigen-activated B-cell blasts that have migrated to the follicles of lymph nodes. The B cells in these structures proliferate and their immunoglobulin genes undergo somatic hypermutation, before the cells leave as plasma cells or memory B cells.

FOLLICULAR DENDRITIC CELLS (FDCs).

Cells with a dendritic morphology that are present in lymph nodes, where they present intact antigens held in immune complexes to B cells.

PLASMABLAST

A dividing B cell that is committed to plasma-cell differentiation.

CLASS-SWITCH RECOMBINATION

DNA rearrangement of the VDJ region from immunoglobulin M to any of the IgG, IgA or IgE constant genes at the heavy-chain locus. Recombination occurs in repetitive sequences of DNA that are located upstream of each constant gene.

SOMATIC HYPERMUTATION

The substitution of 'untemplated' nucleotides or small deletions targeted to a rearranged VDJ or VJ segment, which occurs only in B cells. The mutations are found between the promoter and enhancer of the rearranged gene (including non-coding regions), but they are found at the highest frequency in 'hotspots' (RGYW) that are located in the complementarity-determining regions.

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Shaffer, A., Rosenwald, A. & Staudt, L. Lymphoid Malignancies: the dark side of B-cell differentiation. Nat Rev Immunol 2, 920–933 (2002). https://doi.org/10.1038/nri953

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