Germinal centres: role in B-cell physiology and malignancy (original) (raw)

• MacLennan, I. C. & Gray, D. Antigen-driven selection of virgin and memory B cells. Immunol. Rev. 91, 61–85 (1986).
  Article CAS PubMed Google Scholar
• Jacob, J., Kelsoe, G., Rajewsky, K. & Weiss, U. Intraclonal generation of antibody mutants in germinal centres. Nature 354, 389–392 (1991).
  Article CAS PubMed Google Scholar
• Berek, C., Berger, A. & Apel, M. Maturation of the immune response in germinal centers. Cell 67, 1121–1129 (1991).
  Article CAS PubMed Google Scholar
• MacLennan, I. C. Germinal centers. Annu. Rev. Immunol. 12, 117–139 (1994).
  Article CAS PubMed Google Scholar
• Küppers, R., Klein, U., Hansmann, M. L. & Rajewsky, K. Cellular origin of human B-cell lymphomas. N. Engl. J. Med. 341, 1520–1529 (1999).
  Article PubMed Google Scholar
• Stevenson, F. et al. Insight into the origin and clonal history of B-cell tumors as revealed by analysis of immunoglobulin variable region genes. Immunol. Rev. 162, 247–259 (1998).
  Article CAS PubMed Google Scholar
• Camacho, S. A., Kosco-Vilbois, M. H. & Berek, C. The dynamic structure of the germinal center. Immunol. Today 19, 511–514 (1998).
  Article CAS PubMed Google Scholar
• Wang, Y. & Carter, R. H. CD19 regulates B cell maturation, proliferation, and positive selection in the FDC zone of murine splenic germinal centers. Immunity 22, 749–761 (2005).
  Article CAS PubMed Google Scholar
• Allen, C. D., Okada, T., Tang, H. L. & Cyster, J. G. Imaging of germinal center selection events during affinity maturation. Science 315, 528–531 (2007).
  Article CAS PubMed Google Scholar
• Schwickert, T. A. et al. In vivo imaging of germinal centres reveals a dynamic open structure. Nature 446, 83–87 (2007).
  Article CAS PubMed Google Scholar
• Hauser, A. E. et al. Definition of germinal-center B cell migration in vivo reveals predominant intrazonal circulation patterns. Immunity 26, 655–667 (2007).
  Article CAS PubMed Google Scholar
• Brink, R. Germinal-center B cells in the zone. Immunity 26, 552–554 (2007).
  Article CAS PubMed Google Scholar
• Hauser, A. E., Shlomchik, M. J. & Haberman, A. M. In vivo imaging studies shed light on germinal-centre development. Nature Rev. Immunol. 7, 499–504 (2007).
  Article CAS Google Scholar
• Allen, C. D. et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nature Immunol. 5, 943–952 (2004). This work provided insights into the trafficking of cells between the dark and light zones of GCs and is the first in an elegant series of studies (see references 9,10 and 11 ) that dissects the dynamics of GC B-cell differentiation using sophisticated experimental systems.
  Article CAS Google Scholar
• Klein, U. et al. Transcriptional analysis of the B cell germinal center reaction. Proc. Nat Acad. Sci. USA 100, 2639–2644 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Shaffer, A. L. et al. Signatures of the immune response. Immunity 15, 375–385 (2001).
  Article CAS PubMed Google Scholar
• Phan, R. T. & Dalla-Favera, R. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 432, 635–639 (2004). This study shows that the p53-dependent response to DNA damage normally resulting in growth arrest and apoptotic responses is specifically suppressed in centroblasts by BCL-6.
  Article CAS PubMed Google Scholar
• Hu, B. T., Lee, S. C., Marin, E., Ryan, D. H. & Insel, R. A. Telomerase is up-regulated in human germinal center B cells in vivo and can be re-expressed in memory B cells activated in vitro. J. Immunol. 159, 1068–1071 (1997).
  CAS PubMed Google Scholar
• Liu, Y. J. et al. Mechanism of antigen-driven selection in germinal centres. Nature 342, 929–931 (1989). This is the first demonstration that GC B cells do not survive in vitro unless rescued by CD40 stimulation, thereby providing the first indication that centroblasts are characterized by a pro-apoptotic gene expression programme.
  Article CAS PubMed Google Scholar
• Feuillard, J., Taylor, D., Casamayor-Palleja, M., Johnson, G. D. & MacLennan, I. C. Isolation and characteristics of tonsil centroblasts with reference to Ig class switching. Int. Immunol. 7, 121–130 (1995).
  Article CAS PubMed Google Scholar
• Billian, G., Bella, C., Mondiere, P. & Defrance, T. Identification of a tonsil IgD+ B cell subset with phenotypical and functional characteristics of germinal center B cells. Eur. J. Immunol. 26, 1712–1719 (1996).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Smith, K. G., Nossal, G. J. & Tarlinton, D. M. FAS is highly expressed in the germinal center but is not required for regulation of the B-cell response to antigen. Proc. Natl Acad. Sci. USA 92, 11628–11632 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Takahashi, Y., Ohta, H. & Takemori, T. Fas is required for clonal selection in germinal centers and the subsequent establishment of the memory B cell repertoire. Immunity 14, 181–192 (2001).
  Article CAS PubMed Google Scholar
• de Villartay, J. P., Fischer, A. & Durandy, A. The mechanisms of immune diversification and their disorders. Nature Rev. Immunol. 3, 962–972 (2003).
  Article CAS Google Scholar
• 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
• Basso, K. et al. Tracking CD40 signaling during germinal center development. Blood 104, 4088–4096 (2004).
  Article CAS PubMed Google Scholar
• Kosco-Vilbois, M. H., Bonnefoy, J. Y. & Chvatchko, Y. The physiology of murine germinal center reactions. Immunol. Rev. 156, 127–136 (1997).
  Article CAS PubMed Google Scholar
• Su, G. H. et al. Defective B cell receptor-mediated responses in mice lacking the Ets protein, Spi-B. EMBO J. 16, 7118–7129 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Muto, A. et al. The transcriptional programme of antibody class switching involves the repressor Bach2. Nature 429, 566–571 (2004).
  Article CAS PubMed Google Scholar
• Lee, C. H. et al. Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein. J. Exp. Med. 203, 63–72 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Toyama, H. et al. Memory B cells without somatic hypermutation are generated from Bcl6-deficient B cells. Immunity 17, 329–339 (2002).
  Article CAS PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• Weller, S. et al. Human blood IgM “memory” B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire. Blood 104, 3647–3654 (2004).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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). References 36 and 37 describe for the first time that the somatic hypermutation machinery can act outside the antibody gene loci.
  Article CAS PubMed PubMed Central Google Scholar
• Wagner, S. D. & Neuberger, M. S. Somatic hypermutation of immunoglobulin genes. Annu. Rev. Immunol. 14, 441–457 (1996).
  Article CAS PubMed Google Scholar
• Papavasiliou, F. N. & Schatz, D. G. Cell-cycle-regulated DNA double-stranded breaks in somatic hypermutation of immunoglobulin genes. Nature 408, 216–221 (2000).
  Article CAS PubMed Google Scholar
• Bross, L. et al. DNA double-strand breaks in immunoglobulin genes undergoing somatic hypermutation. Immunity 13, 589–597 (2000).
  Article CAS PubMed Google Scholar
• Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553–563 (2000).
  Article CAS PubMed Google Scholar
• Revy, P. et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 102, 565–575 (2000). References 41 and 42 identify AID as the enzyme required for SHM and CSR.
  Article CAS PubMed Google Scholar
• Petersen-Mahrt, S. K., Harris, R. S. & Neuberger, M. S. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418, 99–103 (2002).
  Article CAS PubMed Google Scholar
• Bransteitter, R., Pham, P., Scharff, M. D. & Goodman, M. F. Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase. Proc. Natl Acad. Sci. USA 100, 4102–4107 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Chaudhuri, J. et al. Transcription-targeted DNA deamination by the AID antibody diversification enzyme. Nature 422, 726–730 (2003).
  Article CAS PubMed Google Scholar
• Di Noia, J. & Neuberger, M. S. Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature 419, 43–48 (2002).
  Article CAS PubMed Google Scholar
• Dickerson, S. K., Market, E., Besmer, E. & Papavasiliou, F. N. AID mediates hypermutation by deaminating single stranded DNA. J. Exp. Med. 197, 1291–1296 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Ramiro, A. R., Stavropoulos, P., Jankovic, M. & Nussenzweig, M. C. Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand. Nature Immunol. 4, 452–456 (2003).
  Article CAS Google Scholar
• Di Noia, J. M. & Neuberger, M. S. Molecular mechanisms of antibody somatic hypermutation. Annu. Rev. Biochem. 76, 1–22 (2007).
  Article CAS PubMed Google Scholar
• Küppers, R., Zhao, M., Hansmann, M. L. & Rajewsky, K. Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J. 12, 4955–4967 (1993).
  Article PubMed PubMed Central Google Scholar
• Pasqualucci, L. et al. Expression of the AID protein in normal and neoplastic B cells. Blood 104, 3318–3325 (2004).
  Article CAS PubMed Google Scholar
• Cattoretti, G. et al. Nuclear and cytoplasmic AID in extrafollicular and germinal center B cells. Blood 107, 3967–3975 (2006).
  Article CAS PubMed Google Scholar
• Sayegh, C. E., Quong, M. W., Agata, Y. & Murre, C. E-proteins directly regulate expression of activation-induced deaminase in mature B cells. Nature Immunol. 4, 586–593 (2003).
  Article CAS Google Scholar
• Gonda, H. et al. The balance between Pax5 and Id2 activities is the key to AID gene expression. J. Exp. Med. 198, 1427–1437 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Chaudhuri, J., Khuong, C. & Alt, F. W. Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature 430, 992–998 (2004).
  Article CAS PubMed Google Scholar
• Basu, U. et al. The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation. Nature 438, 508–511 (2005).
  Article CAS PubMed Google Scholar
• Pasqualucci, L., Kitaura, Y., Gu, H. & Dalla-Favera, R. PKA-mediated phosphorylation regulates the function of activation-induced deaminase (AID) in B cells. Proc. Natl Acad. Sci. USA 103, 395–400 (2006).
  Article CAS PubMed Google Scholar
• McBride, K. M. et al. Regulation of hypermutation by activation-induced cytidine deaminase phosphorylation. Proc. Natl Acad. Sci. USA 103, 8798–8803 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Pasqualucci, L. et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412, 341–346 (2001). This is the first demonstration that proto-oncogenes in a certain type of lymphoma are frequently hypermutated in their promoter region, and may contribute to lymphomagenesis by causing dysregulated expression.
  Article CAS PubMed Google Scholar
• Ye, B. H. et al. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science 262, 747–750 (1993).
  Article CAS PubMed Google Scholar
• Cattoretti, G. et al. BCL-6 protein is expressed in germinal-center B cells. Blood 86, 45–53 (1995).
  CAS PubMed Google Scholar
• Allman, D. et al. BCL-6 expression during B-cell activation. Blood 87, 5257–5268 (1996).
  CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Ye, B. H. et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nature Genet. 16, 161–170 (1997). References 63 and 64 show that the BCL6 proto-oncogene is required for the formation of GCs in T-cell-dependent immune responses.
  Article CAS PubMed Google Scholar
• Cattoretti, G. et al. Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer Cell 7, 445–455 (2005).
  Article CAS PubMed Google Scholar
• Polo, J. M. et al. Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells. Nature Med. 10, 1329–1335 (2004).
  Article CAS PubMed Google Scholar
• Fujita, N. et al. MTA3 and the Mi-2/NuRD complex regulate cell fate during B lymphocyte differentiation. Cell 119, 75–86 (2004).
  Article CAS PubMed Google Scholar
• Parekh, S. et al. BCL6 programs lymphoma cells for survival and differentiation through distinct biochemical mechanisms. Blood 110, 2067–2074 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Shaffer, A. L. et al. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13, 199–212 (2000). This study employs an elegant global gene expression-profiling approach to identify BCL-6 target genes, providing novel insights into BCL-6 function.
  Article CAS PubMed Google Scholar
• Niu, H., Cattoretti, G. & Dalla-Favera, R. BCL6 controls the expression of the B7–1/CD80 costimulatory receptor in germinal center B cells. J. Exp. Med. 198, 211–221 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Phan, R. T., Saito, M., Basso, K., Niu, H. & Dalla-Favera, R. BCL6 interacts with the transcription factor Miz-1 to suppress the cyclin-dependent kinase inhibitor p21 and cell cycle arrest in germinal center B cells. Nature Immunol. 6, 1054–1060 (2005).
  Article CAS Google Scholar
• Ranuncolo, S. M. et al. Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR. Nature Immunol. 8, 705–714 (2007).
  Article CAS Google Scholar
• Phan, R. T., Saito, M., Kitagawa, Y., Means, A. & Dalla-Favera, R. Genotoxic stress regulates expression of the BCL6 proto-oncogene in germinal center B cells. Nature Immunol. 8, 1132–1139 (2007).
  Article CAS Google Scholar
• Tunyaplin, C. et al. Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J. Immunol. 173, 1158–1165 (2004).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Shapiro-Shelef, M. et al. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19, 607–620 (2003). References 76 and 77 show that the transcriptional repressor BLIMP1 is essential for the terminal differentiation of a B cell into a plasma cell.
  Article CAS PubMed Google Scholar
• Kuo, T. C. et al. Repression of BCL-6 is required for the formation of human memory B cells in vitro. J. Exp. Med. 204, 819–830 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Saito, M. et al. A signaling pathway mediating down-regulation of BCL6 in germinal center B-cells is blocked by BCL6 gene alterations in B-cell lymphoma. Cancer Cell 12, 280–292 (2007).
  Article CAS PubMed Google Scholar
• Bereshchenko, O. R., Gu, W. & Dalla-Favera, R. Acetylation inactivates the transcriptional repressor BCL6. Nature Genet. 32, 606–613 (2002).
  Article CAS PubMed Google Scholar
• Blink, E. J. et al. Early appearance of germinal center-derived memory B cells and plasma cells in blood after primary immunization. J. Exp. Med. 201, 545–554 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Shih, T. A., Meffre, E., Roederer, M. & Nussenzweig, M. C. Role of BCR affinity in T cell dependent antibody responses in vivo. Nature Immunol. 3, 570–575 (2002).
  Article CAS Google Scholar
• Phan, T. G. et al. High affinity germinal center B cells are actively selected into the plasma cell compartment. J. Exp. Med. 203, 2419–2424 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Barreto, V., Reina-San-Martin, B., Ramiro, A. R., McBride, K. M. & Nussenzweig, M. C. C-terminal deletion of AID uncouples class switch recombination from somatic hypermutation and gene conversion. Mol. Cell 12, 501–508 (2003).
  Article CAS PubMed Google Scholar
• Ta, V. T. et al. AID mutant analyses indicate requirement for class-switch-specific cofactors. Nature Immunol. 4, 843–848 (2003).
  Article CAS Google Scholar
• Rooney, S., Chaudhuri, J. & Alt, F. W. The role of the non-homologous end-joining pathway in lymphocyte development. Immunol. Rev. 200, 115–131 (2004).
  Article CAS PubMed Google Scholar
• Liu, Y. J. et al. Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. Immunity 4, 241–250 (1996).
  Article CAS PubMed Google Scholar
• Tafuri, A. et al. ICOS is essential for effective T-helper-cell responses. Nature 409, 105–109 (2001).
  Article CAS PubMed Google Scholar
• McAdam, A. J. et al. ICOS is critical for CD40-mediated antibody class switching. Nature 409, 102–105 (2001).
  Article CAS PubMed Google Scholar
• Castigli, E. et al. TACI and BAFF-R mediate isotype switching in B cells. J. Exp. Med. 201, 35–39 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Klein, U. et al. IRF4 controls plasma cell differentiation and class switch recombination. Nature Immunol. 7, 773–782 (2006).
  Article CAS Google Scholar
• Sciammas, R. et al. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 25, 225–236 (2006).
  Article CAS PubMed Google Scholar
• Liu, Y. J. & Banchereau, J. Regulation of B-cell commitment to plasma cells or to memory B cells. Semin. Immunol. 9, 235–240 (1997).
  Article CAS PubMed Google Scholar
• Shan, H., Shlomchik, M. & Weigert, M. Heavy-chain class switch does not terminate somatic mutation. J. Exp. Med. 172, 531–536 (1990).
  Article CAS PubMed Google Scholar
• Cobaleda, C., Schebesta, A., Delogu, A. & Busslinger, M. Pax5: the guardian of B cell identity and function. Nature Immunol. 8, 463–470 (2007).
  Article CAS Google Scholar
• Delogu, A. et al. Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells. Immunity 24, 269–281 (2006).
  Article CAS PubMed Google Scholar
• Nera, K. P. et al. Loss of Pax5 promotes plasma cell differentiation. Immunity 24, 283–293 (2006).
  Article CAS PubMed Google Scholar
• Kallies, A. et al. Initiation of plasma-cell differentiation is independent of the transcription factor blimp-1. Immunity 26, 555–566 (2007). This study demonstrates that the earliest step in plasma-cell differentiation is mediated by the downregulation of PAX5, followed by BLIMP1 upregulation.
  Article CAS PubMed Google Scholar
• 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
• 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).
  Article CAS PubMed Google Scholar
• Reimold, A. M. et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature 412, 300–307 (2001).
  Article CAS PubMed Google Scholar
• Shaffer, A. L. et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 21, 81–93 (2004).
  Article CAS PubMed Google Scholar
• Mittrücker, H. W. et al. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 275, 540–543 (1997).
  Article PubMed Google Scholar
• Fornek, J. L. et al. Critical role for Stat3 in T-dependent terminal differentiation of IgG B cells. Blood 107, 1085–1091 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Scheeren, F. A. et al. STAT5 regulates the self-renewal capacity and differentiation of human memory B cells and controls Bcl-6 expression. Nature Immunol. 6, 303–313 (2005).
  Article CAS Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Arpin, C. et al. Generation of memory B cells and plasma cells in vitro. Science 268, 720–722 (1995).
  Article CAS PubMed Google Scholar
• Stevenson, F. et al. Insight into the origin and clonal history of B-cell tumors as revealed by analysis of immunoglobulin variable region genes. Immunol. Rev. 162, 247–259 (1998).
  Article CAS PubMed Google Scholar
• Küppers, R. & Dalla-Favera, R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 20, 5580–5594 (2001).
  Article PubMed Google Scholar
• Küppers, R. Mechanisms of B-cell lymphoma pathogenesis. Nature Rev. Cancer 5, 251–262 (2005).
  Article CAS Google Scholar
• Lenz, G. et al. Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma. J. Exp. Med. 204, 633–643 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Pasqualucci, L. et al. Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood 101, 2914–2923 (2003).
  Article CAS PubMed Google Scholar
• Okazaki, I. M. et al. Constitutive expression of AID leads to tumorigenesis. J. Exp. Med. 197, 1173–1181 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Ramiro, A. R. et al. AID is required for c-myc/IgH chromosome translocations in vivo. Cell 118, 431–438 (2004).
  Article CAS PubMed Google Scholar
• Unniraman, S., Zhou, S. & Schatz, D. G. Identification of an AID-independent pathway for chromosomal translocations between the Igh switch region and Myc. Nature Immunol. 5, 1117–1123 (2004).
  Article CAS Google Scholar
• Franco, S. et al. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol. Cell 21, 201–214 (2006).
  Article CAS PubMed Google Scholar
• Kotani, A. et al. Activation-induced cytidine deaminase (AID) promotes B cell lymphomagenesis in Emu-cmyc transgenic mice. Proc. Natl Acad. Sci. USA 104, 1616–1620 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Pasqualucci, L. et al. Activation induced cytidine deaminase (AID) is required for germinal-center-derived lymphomagenesis. Nature Genet. 9 December 2007 (doi:10.1038/ng.2007.35) References 118 and 119 identify AID as being crucially involved in the pathogenesis of GC-derived B-cell lymphomas.
• McDonnell, T. J. & Korsmeyer, S. J. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature 349, 254–256 (1991).
  Article CAS PubMed Google Scholar
• 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
• Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).
  Article CAS PubMed Google Scholar
• Vafa, O. et al. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol. Cell 9, 1031–1044 (2002).
  Article CAS PubMed Google Scholar
• Dominguez-Sola, D. et al. Non-transcriptional control of DNA replication by c-Myc. Nature 448, 445–451 (2007).
  Article CAS PubMed Google Scholar
• Tam, W. et al. Mutational analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell lymphomas. Blood 107, 4090–4100 (2006).
  Article CAS PubMed Google Scholar
• Pasqualucci, L. et al. Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma. J. Exp. Med. 203, 311–317 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Thai, T. H. et al. Regulation of the germinal center response by microRNA-155. Science 316, 604–608 (2007).
  Article CAS PubMed Google Scholar
• Rodriguez, A. et al. Requirement of bic/microRNA-155 for normal immune function. Science 316, 608–611 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Goossens, T., Klein, U. & Küppers, 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).
  Article CAS PubMed PubMed Central Google Scholar
• Toellner, K. M., Gulbranson-Judge, A., Taylor, D. R., Sze, D. M. & MacLennan, I. C. Immunoglobulin switch transcript production in vivo related to the site and time of antigen-specific B cell activation. J. Exp. Med. 183, 2303–2312 (1996).
  Article CAS PubMed Google Scholar
• Seki, M., Gearhart, P. J. & Wood, R. D. DNA polymerases and somatic hypermutation of immunoglobulin genes. EMBO Rep. 6, 1143–1148 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Martin, A. & Scharff, M. D. AID and mismatch repair in antibody diversification. Nature Rev. Immunol. 2, 605–614 (2002).
  Article CAS Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar