The germinal centre (GC) is the histological structure dedicated to the generation and selection of B cells that produce high-affinity antibodies. It also represents the site from which most B cell lymphomas originate.
The GC is functionally polarized — the dark zone is the site of B cell divisions and immunoglobulin somatic hypermutation, whereas the light zone is where B cells undergo activation and selection on the basis of the affinity of their immunoglobulin. B cells undergo multiple cycles of re-entry between the light zone and the dark zone.
The initiation of the GC reaction is dependent on the induction of several transcriptional modulators, a subset of which is affected by genetic alterations in lymphomas. These modulators include several transcription factors — MYC, myocyte-specific enhancer factor 2B (MEF2B), B cell lymphoma 6 (BCL-6), E2A, nuclear factor-κB (NF-κB) and interferon-regulatory factor 4 (IRF4) — and the chromatin modifier enhancer of zeste homologue 2 (EZH2).
Following the initial peak of expression, MYC is silenced in most GC B cells and is briefly reactivated in a very small subset of light zone B cells that are primed for re-entry into the dark zone compartment. NF-κB is absent in dark zone B cells, whereas it contributes to B cell selection and differentiation in the light zone. IRF4 is re-expressed in a subset of light zone B cells that are committed to plasma cell differentiation.
B cell non-Hodgkin lymphomas (B-NHLs) comprise a range of genetically, phenotypically and clinically distinct malignancies, the majority of which derive from GC B cells. Burkitt lymphoma originates from dark zone B cells, follicular lymphoma and the GC B cell (GCB)-like subtype of diffuse large B cell lymphoma (DLBCL) resemble light zone B cells, and the activated B cell (ABC)-like subtype of DLBCL shows features of cells arrested at the plasmablast stage.
DLBCLs comprise at least two distinct entities: GCB-DLBCL and ABC-DLBCL. Although GCB-DLBCL and ABC-DLBCL share several alterations — including those involving chromatin modifiers, BCL-6 dysregulation and immune recognition — each DLBCL subtype has specific genetic aberrations. GCB-DLBCLs carry lesions affecting MYC and/or BCL2, promoting aberrant EZH2 activity and altering B cell migration. ABC-DLBCLs are characterized by constitutive activation of NF-κB and a blockade of terminal differentiation.
Germinal centres (GCs) are involved in the selection of B cells secreting high-affinity antibodies and are also the origin of most human B cell lymphomas. Recent progress has been made in identifying the functionally relevant stages of the GC and the complex trafficking mechanisms of B cells within the GC. These studies have identified transcription factors and signalling pathways that regulate distinct phases of GC development. Notably, these factors and pathways are hijacked during tumorigenesis, as revealed by analyses of the genetic lesions associated with various types of B cell lymphomas. This Review focuses on recent insights into the mechanisms that regulate GC development and that are relevant for human B cell lymphomagenesis.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Oncogene Open Access 06 September 2022
ALKBH5-mediated N6-methyladenosine modification of TRERNA1 promotes DLBCL proliferation via p21 downregulation
Cell Death Discovery Open Access 14 January 2022
Inhibitors of Bcl-2 and Bruton’s tyrosine kinase synergize to abrogate diffuse large B-cell lymphoma growth in vitro and in orthotopic xenotransplantation models
Leukemia Open Access 18 November 2021
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Klein, U. & Dalla-Favera, R. Germinal centres: role in B-cell physiology and malignancy. Nature Rev. Immunol. 8, 22–33 (2008).
MacLennan, I. C. Germinal centers. Annu. Rev. Immunol. 12, 117–139 (1994).
Victora, G. D. & Nussenzweig, M. C. Germinal centers. Annu. Rev. Immunol. 30, 429–457 (2012).
Kuppers, R. Mechanisms of B-cell lymphoma pathogenesis. Nature Rev. Cancer 5, 251–262 (2005).
Kuppers, R. & Dalla-Favera, R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 20, 5580–5594 (2001).
Victora, G. D. et al. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143, 592–605 (2010). This study characterizes GC B cells in the dark zone and the light zone, which lead to the conclusive evidence that these compartments are functionally distinct.
Victora, G. D. et al. Identification of human germinal center light and dark zone cells and their relationship to human B-cell lymphomas. Blood 120, 2240–2248 (2012). This study provides the first molecular characterization of human dark zone and light zone B cells and investigates the relationship of GC-derived lymphomas with their normal counterparts.
Lohr, J. G. et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc. Natl Acad. Sci. USA 109, 3879–3884 (2012).
Morin, R. D. et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476, 298–303 (2011).
Pasqualucci, L. et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nature Genet. 43, 830–837 (2011). References 8, 9 and 10 are the first reports describing the coding genomes of the most common B-NHLs, including DLBCL and follicular lymphoma.
Zhang, J. et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc. Natl Acad. Sci. USA 110, 1398–1403 (2013).
Richter, J. et al. Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nature Genet. 44, 1316–1320 (2012).
Schmitz, R. et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature 490, 116–120 (2012). References 12 and 13 are the first reports describing the coding genome of Burkitt lymphoma.
De Silva, N. & Klein, U. Dynamics of B cells in the germinal centre. Nature Rev. Immunol. 15, 137–148 (2015).
Scott, D. W. & Gascoyne, R. D. The tumour microenvironment in B cell lymphomas. Nature Rev. Cancer 14, 517–534 (2014).
Dalla-Favera, R. et al. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc. Natl Acad. Sci. USA 79, 7824–7827 (1982).
Taub, R. et al. Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc. Natl Acad. Sci. USA 79, 7837–7841 (1982).
Calado, D. P. et al. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nature Immunol. 13, 1092–1100 (2012).
Dominguez-Sola, D. et al. The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nature Immunol. 13, 1083–1091 (2012). References 18 and 19 show the role of MYC in the initiation of the GC reaction and during the selection and cyclic re-entry of light zone B cells.
Klein, U. et al. Transcriptional analysis of the B cell germinal center reaction. Proc. Natl Acad. Sci. USA 100, 2639–2644 (2003).
Shaffer, A. L. et al. Signatures of the immune response. Immunity 15, 375–385 (2001).
Lin, C. Y. et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell 151, 56–67 (2012).
Nie, Z. et al. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151, 68–79 (2012).
Conacci-Sorrell, M., McFerrin, L. & Eisenman, R. N. An overview of MYC and its interactome. Cold Spring Harb. Perspect. Med. 4, a014357 (2014).
Ying, C. Y. et al. MEF2B mutations lead to deregulated expression of the oncogene BCL6 in diffuse large B cell lymphoma. Nature Immunol. 14, 1084–1092 (2013).
Basso, K. & Dalla-Favera, R. Roles of BCL6 in normal and transformed germinal center B cells. Immunol. Rev. 247, 172–183 (2012).
Kerfoot, S. M. et al. Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone. Immunity 34, 947–960 (2011).
Kitano, M. et al. Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity. Immunity 34, 961–972 (2011).
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).
Ochiai, K. et al. Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4. Immunity 38, 918–929 (2013).
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).
Hatzi, K. et al. A hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters. Cell Rep. 4, 578–588 (2013).
Hatzi, K. & Melnick, A. Breaking bad in the germinal center: how deregulation of BCL6 contributes to lymphomagenesis. Trends Mol. Med. 20, 343–352 (2014).
Huang, C. et al. The BCL6 RD2 domain governs commitment of activated B cells to form germinal centers. Cell Rep. 8, 1497–1508 (2014).
Huang, C., Hatzi, K. & Melnick, A. Lineage-specific functions of Bcl-6 in immunity and inflammation are mediated by distinct biochemical mechanisms. Nature Immunol. 14, 380–388 (2013).
Basso, K. et al. Integrated biochemical and computational approach identifies BCL6 direct target genes controlling multiple pathways in normal germinal center B cells. Blood 115, 975–984 (2010).
Ci, W. et al. The BCL6 transcriptional program features repression of multiple oncogenes in primary B cells and is deregulated in DLBCL. Blood 113, 5536–5548 (2009). References 36 and 37 are the first reports on the genome-wide dissection of the BCL-6 transcriptional network in GC B cells.
Basso, K. et al. BCL6 positively regulates AID and germinal center gene expression via repression of miR-155. J. Exp. Med. 209, 2455–2465 (2012).
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).
Ye, B. H. et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nature Genet. 16, 161–170 (1997).
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).
Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039–1043 (2002).
Czermin, B. et al. Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell 111, 185–196 (2002).
Muller, J. et al. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 111, 197–208 (2002).
Su, I. H. et al. Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nature Immunol. 4, 124–131 (2003).
van Galen, J. C. et al. Distinct expression patterns of polycomb oncoproteins and their binding partners during the germinal center reaction. Eur. J. Immunol. 34, 1870–1881 (2004).
Beguelin, W. et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23, 677–692 (2013).
Caganova, M. et al. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J. Clin. Invest. 123, 5009–5022 (2013). References 47 and 48 provide in vivo validation that EZH2 is required for GC formation and that its genetic activation contributes to lymphomagenesis.
Velichutina, I. et al. EZH2-mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis. Blood 116, 5247–5255 (2010).
Kee, B. L. E and ID proteins branch out. Nature Rev. Immunol. 9, 175–184 (2009).
Kwon, K. et al. Instructive role of the transcription factor E2A in early B lymphopoiesis and germinal center B cell development. Immunity 28, 751–762 (2008).
Willis, S. N. et al. Transcription factor IRF4 regulates germinal center cell formation through a B cell-intrinsic mechanism. J. Immunol. 192, 3200–3206 (2014).
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).
Basso, K. et al. Tracking CD40 signaling during germinal center development. Blood 104, 4088–4096 (2004).
Vallabhapurapu, S. & Karin, M. Regulation and function of NF-κB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693–733 (2009).
Heise, N. et al. Germinal center B cell maintenance and differentiation are controlled by distinct NF-κB transcription factor subunits. J. Exp. Med. 211, 2103–2118 (2014).
Saito, M. et al. A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell 12, 280–292 (2007).
Chu, Y. et al. B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice. Blood 117, 2227–2236 (2011).
Tavares, R. M. et al. The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity. Immunity 33, 181–191 (2010).
Klein, U. et al. Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nature Immunol. 7, 773–782 (2006).
Sciammas, R. et al. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 25, 225–236 (2006). References 30, 60 and 61 discuss the role of IRF4 during the GC initiation, CSR and plasma cell differentiation.
Tunyaplin, C. et al. Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J. Immunol. 173, 1158–1165 (2004).
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).
Duan, S. et al. FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas. Nature 481, 90–93 (2012).
Bereshchenko, O. R., Gu, W. & Dalla-Favera, R. Acetylation inactivates the transcriptional repressor BCL6. Nature Genet. 32, 606–613 (2002).
Nutt, S. L., Taubenheim, N., Hasbold, J., Corcoran, L. M. & Hodgkin, P. D. The genetic network controlling plasma cell differentiation. Semin. Immunol. 23, 341–349 (2011).
Cobaleda, C., Schebesta, A., Delogu, A. & Busslinger, M. Pax5: the guardian of B cell identity and function. Nature Immunol. 8, 463–470 (2007).
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).
Nera, K. P. et al. Loss of Pax5 promotes plasma cell differentiation. Immunity 24, 283–293 (2006).
Nutt, S. L., Hodgkin, P. D., Tarlinton, D. M., Corcoran, L. M. The generation of antibody-secreting plasma cells. Nature Rev. Immunol. 15, 160–171 (2015).
Kwon, H. et al. Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity 31, 941–952 (2009).
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).
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).
Cimmino, L. et al. Blimp-1 attenuates Th1 differentiation by repression of ifng, tbx21, and bcl6 gene expression. J. Immunol. 181, 2338–2347 (2008).
Kallies, A. et al. Initiation of plasma-cell differentiation is independent of the transcription factor Blimp-1. Immunity 26, 555–566 (2007).
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).
Hu, C. C., Dougan, S. K., McGehee, A. M., Love, J. C. & Ploegh, H. L. XBP-1 regulates signal transduction, transcription factors and bone marrow colonization in B cells. EMBO J. 28, 1624–1636 (2009).
Reimold, A. M. et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature 412, 300–307 (2001).
Kuppers, R., Klein, U., Hansmann, M. L. & Rajewsky, K. Cellular origin of human B-cell lymphomas. N. Engl. J. Med. 341, 1520–1529 (1999).
Stevenson, F. K. et al. The occurrence and significance of V gene mutations in B cell-derived human malignancy. Adv. Cancer Res. 83, 81–116 (2001).
Dave, S. S. et al. Molecular diagnosis of Burkitt's lymphoma. N. Engl. J. Med. 354, 2431–2442 (2006).
Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).
Rosenwald, A. et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J. Exp. Med. 198, 851–862 (2003).
Dierlamm, J. et al. The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood 93, 3601–3609 (1999).
Morgan, J. A. et al. Breakpoints of the t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma lie within or near the previously undescribed gene MALT1 in chromosome 18. Cancer Res. 59, 6205–6213 (1999).
Scott, D. W. et al. TBL1XR1/TP63: a novel recurrent gene fusion in B-cell non-Hodgkin lymphoma. Blood 119, 4949–4952 (2012).
Dorsett, Y. et al. A role for AID in chromosome translocations between c-myc and the IgH variable region. J. Exp. Med. 204, 2225–2232 (2007).
Pasqualucci, L. et al. AID is required for germinal center-derived lymphomagenesis. Nature Genet. 40, 108–112 (2008).
Pasqualucci, L. et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412, 341–346 (2001).
Muschen, M. et al. Somatic mutation of the CD95 gene in human B cells as a side-effect of the germinal center reaction. J. Exp. Med. 192, 1833–1840 (2000).
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).
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).
Khodabakhshi, A. H. et al. Recurrent targets of aberrant somatic hypermutation in lymphoma. Oncotarget 3, 1308–1319 (2012).
Schmitz, R., Ceribelli, M., Pittaluga, S., Wright, G. & Staudt, L. M. Oncogenic mechanisms in Burkitt lymphoma. Cold Spring Harb. Perspect. Med. 4, a014282 (2014).
Muppidi, J. R. et al. Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma. Nature 516, 254–258 (2014).
Nussenzweig, A. & Nussenzweig, M. C. Origin of chromosomal translocations in lymphoid cancer. Cell 141, 27–38 (2010).
Dominguez-Sola, D. et al. Non-transcriptional control of DNA replication by c-Myc. Nature 448, 445–451 (2007).
Srinivasan, L. et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell 139, 573–586 (2009).
Peled, J. U. et al. Requirement for cyclin D3 in germinal center formation and function. Cell Res. 20, 631–646 (2010).
Sander, S. et al. Synergy between PI3K signaling and MYC in Burkitt lymphomagenesis. Cancer Cell 22, 167–179 (2012). This study shows that the pathogenesis of Burkitt lymphoma requires both ectopic expression of MYC and activation of the PI3K signalling pathway in vivo.
Kridel, R., Sehn, L. H. & Gascoyne, R. D. Pathogenesis of follicular lymphoma. J. Clin. Invest. 122, 3424–3431 (2012).
Montoto, S. & Fitzgibbon, J. Transformation of indolent B-cell lymphomas. J. Clin. Oncol. 29, 1827–1834 (2011).
McCann, K. J., Johnson, P. W., Stevenson, F. K. & Ottensmeier, C. H. Universal N-glycosylation sites introduced into the B-cell receptor of follicular lymphoma by somatic mutation: a second tumorigenic event? Leukemia 20, 530–534 (2006).
Saito, M. et al. BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma. Proc. Natl Acad. Sci. USA 106, 11294–11299 (2009).
Czabotar, P. E., Lessene, G., Strasser, A. & Adams, J. M. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nature Rev. Mol. Cell Biol. 15, 49–63 (2014).
Sungalee, S. et al. Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression. J. Clin. Invest. 124, 5337–5351 (2014).
Okosun, J. et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nature Genet. 46, 176–181 (2014).
Pasqualucci, L. et al. Genetics of follicular lymphoma transformation. Cell Rep. 6, 130–140 (2014).
Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nature Genet. 42, 181–185 (2010). This is the first report to identify EZH2 mutations in B-NHLs.
Bodor, C. et al. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood 122, 3165–3168 (2013).
Pasqualucci, L. et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471, 189–195 (2011). Along with reference 9, this study reports on the frequent genetic alterations targeting the CREBBP and/or EP300 genes, and functionally characterizes their role in lymphomagenesis.
Jamroziak, K., Tadmor, T., Robak, T. & Polliack, A. Richter syndrome in chronic lymphocytic leukemia: updates on biology, clinical features and therapy. Leuk. Lymphoma 21, 1–10 (2015).
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).
Ye, B. H. et al. Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma. EMBO J. 14, 6209–6217 (1995).
Chen, W., Iida, S., Louie, D. C., Dalla-Favera, R. & Chaganti, R. S. Heterologous promoters fused to BCL6 by chromosomal translocations affecting band 3q27 cause its deregulated expression during B-cell differentiation. Blood 91, 603–607 (1998).
Challa-Malladi, M. et al. Combined genetic inactivation of β2-Microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell 20, 728–740 (2011). This study provides the first genetic explanation behind the immune privileges of lymphoma cells.
Fangazio, M. D.-S. et al. Genetic mechanisms of immune escape in diffuse large B cell lymphoma. Blood Abstr. 124, 1692 (2014).
de Miranda, N. F. et al. Exome sequencing reveals novel mutation targets in diffuse large B-cell lymphomas derived from Chinese patients. Blood 124, 2544–2553 (2014).
Aukema, S. M. et al. Double-hit B-cell lymphomas. Blood 117, 2319–2331 (2011).
Li, S. et al. MYC/BCL2 double-hit high-grade B-cell lymphoma. Adv. Anat. Pathol. 20, 315–326 (2013).
Sneeringer, C. J. et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc. Natl Acad. Sci. USA 107, 20980–20985 (2010).
Green, J. A. et al. The sphingosine 1-phosphate receptor S1P(2) maintains the homeostasis of germinal center B cells and promotes niche confinement. Nature Immunol. 12, 672–680 (2011).
Cattoretti, G. et al. Targeted disruption of the S1P2 sphingosine 1-phosphate receptor gene leads to diffuse large B-cell lymphoma formation. Cancer Res. 69, 8686–8692 (2009).
Davis, R. E. et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463, 88–92 (2010).
Lenz, G. et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 319, 1676–1679 (2008).
Ngo, V. N. et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 470, 115–119 (2011).
Lin, S. C., Lo, Y. C. & Wu, H. Helical assembly in the MyD88–IRAK4–IRAK2 complex in TLR/IL-1R signalling. Nature 465, 885–890 (2010).
Wang, J. Q., Jeelall, Y. S., Beutler, B., Horikawa, K. & Goodnow, C. C. Consequences of the recurrent MYD88L265P somatic mutation for B cell tolerance. J. Exp. Med. 211, 413–426 (2014).
Compagno, M. et al. Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma. Nature 459, 717–721 (2009). References 124, 125, 126 and 129 provide the genetic evidence that ABC-DLBCL cells rely on NF- κ B aberrant activation through multiple mechanisms.
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).
Mandelbaum, J. et al. BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. Cancer Cell 18, 568–579 (2010).
Pasqualucci, L. et al. Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma. J. Exp. Med. 203, 311–317 (2006).
Tam, W. et al. Mutational analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell lymphomas. Blood 107, 4090–4100 (2006). References 132 and 133 identify frequent genetic lesion targeting the PRDM1 gene in DLBCL and reference 131 provides in vivo evidence that BLIMP1 functions as a tumour suppressor.
Iqbal, J. et al. Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma. Leukemia 21, 2332–2343 (2007).
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).
Lenz, G. et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc. Natl Acad. Sci. USA 105, 13520–13525 (2008).
Care, M. A. et al. SPIB and BATF provide alternate determinants of IRF4 occupancy in diffuse large B-cell lymphoma linked to disease heterogeneity. Nucleic Acids Res. 42, 7591–7610 (2014).
Schmidlin, H. et al. Spi-B inhibits human plasma cell differentiation by repressing BLIMP1 and XBP-1 expression. Blood 112, 1804–1812 (2008).
Yang, Y. et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell 21, 723–737 (2012).
Calado, D. P. et al. Constitutive canonical NF-κB activation cooperates with disruption of BLIMP1 in the pathogenesis of activated B cell-like diffuse large cell lymphoma. Cancer Cell 18, 580–589 (2010).
Abramson, J. S. & Shipp, M. A. Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach. Blood 106, 1164–1174 (2005).
Shaffer, A. L. 3rd, Young, R. M. & Staudt, L. M. Pathogenesis of human B cell lymphomas. Annu. Rev. Immunol. 30, 565–610 (2012).
Delmore, J. E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904–917 (2011).
Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067–1073 (2010).
Mertz, J. A. et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc. Natl Acad. Sci. USA 108, 16669–16674 (2011).
Hoellenriegel, J. et al. The phosphoinositide 3′-kinase δ inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood 118, 3603–3612 (2011).
Anderson, M. A., Huang, D. & Roberts, A. Targeting BCL2 for the treatment of lymphoid malignancies. Semin. Hematol. 51, 219–227 (2014).
Knutson, S. K. et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nature Chem. Biol. 8, 890–896 (2012).
McCabe, M. T. et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492, 108–112 (2012).
Qi, W. et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc. Natl Acad. Sci. USA 109, 21360–21365 (2012).
Verma, S. K. et al. Identification of potent, selective, cell-active inhibitors of the histone lysine methyltransferase EZH2. ACS Med. Chem. Lett. 3, 1091–1096 (2012).
Berek, C., Berger, A. & Apel, M. Maturation of the immune response in germinal centers. Cell 67, 1121–1129 (1991).
Jacob, J., Kelsoe, G., Rajewsky, K. & Weiss, U. Intraclonal generation of antibody mutants in germinal centres. Nature 354, 389–392 (1991).
Allen, C. D. et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nature Immunol. 5, 943–952 (2004). Reference 154 provides insights into cell trafficking between the dark and light zones, and is the first of a series of studies (see references 6, 156 and 157) that dissect the dynamics of B cells during the GC reaction using intravital imaging.
Caron, G., Le Gallou, S., Lamy, T., Tarte, K. & Fest, T. CXCR4 expression functionally discriminates centroblasts versus centrocytes within human germinal center B cells. J. Immunol. 182, 7595–7602 (2009).
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).
Schwickert, T. A. et al. In vivo imaging of germinal centres reveals a dynamic open structure. Nature 446, 83–87 (2007).
The authors thank all the members of their laboratories for their contribution to the generation of data reported in this manuscript, and apologize to those whose work could not be described or cited owing to space limitations.
The authors declare no competing financial interests.
- Dark zone
A histological and functional compartment of the germinal centre in which B cells proliferate extensively and undergo immunoglobulin somatic hypermutation.
- Immunoglobulin somatic hypermutation
(SHM). A genetic mechanism that introduces mainly single nucleotide exchanges in a region encompassing ~2 kb from the transcriptional start site of the genes encoding the variable regions of the immunoglobulin receptors.
- Light zone
A histological and functional compartment of the germinal centre in which B cells are selected on the basis of their affinity for the antigen.
Short single-stranded RNAs that negatively modulate gene expression at the post-transcriptional level.
- Ubiquitin ligase complex
A protein complex that is involved in the recruitment, ubiquitylation and proteasome-mediated degradation of proteins.
- Aberrant SHMs
(ASHMs). Mutations that occur as a result of the aberrant function of the physiological immunoglobulin somatic hypermutation (SHM) mechanism, when its activity is extended to non-immunoglobulin loci that are not targeted in normal germinal centre B cells.
- V(D)J recombination
A genetic mechanism that recombines the immunoglobulin loci to place one variable (V), one diversity (D) and one joining (J) gene next to each other. The D genes are found in the heavy chain locus, but not in the light chain loci.
- Recombination-activating gene
(RAG). RAG1 and RAG2 are involved in the initial steps of V(D)J recombination by binding to specific recognition sequences and generating single-stranded DNA breaks.
- Activation-induced cytidine deaminase
(AID). An enzyme that deaminates DNA cytidines leading to the formation of U:G pairs, which become targets of the repair machinery. AID is involved in somatic hypermutation and class-switch recombination.
- Sporadic Burkitt lymphoma
A subtype of Burkitt lymphoma that is characterized by a sporadic worldwide distribution.
- Endemic Burkitt lymphoma
A subtype of Burkitt lymphoma that is common in the sub-Saharan regions of Africa and is associated with Epstein–Barr virus infection in 100% of cases.
- 'Tonic' BCR signalling
Antigen-independent B cell receptor (BCR) signalling that mainly functions through activation of the phosphoinositide 3-kinase (PI3K) pathway and that is required for the survival of mature B cells in the periphery.
- Cancer epigenome
A combination of chemical changes that target DNA and histones, and that affect gene expression in tumour cells without altering the coding sequence.
A signalling hub consisting of caspase recruitment domain-containing protein 11 (CARD11), B cell lymphoma 10 (BCL-10), mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) and other proteins that is required for the activation of the classical nuclear factor-κB pathway downstream of the B cell receptor.
About this article
Cite this article
Basso, K., Dalla-Favera, R. Germinal centres and B cell lymphomagenesis. Nat Rev Immunol 15, 172–184 (2015). https://doi.org/10.1038/nri3814
This article is cited by
ALKBH5-mediated N6-methyladenosine modification of TRERNA1 promotes DLBCL proliferation via p21 downregulation
Cell Death Discovery (2022)
Nature Immunology (2022)
Inhibitors of Bcl-2 and Bruton’s tyrosine kinase synergize to abrogate diffuse large B-cell lymphoma growth in vitro and in orthotopic xenotransplantation models
Journal of Clinical Immunology (2022)