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Germinal centres and B cell lymphomagenesis

Key Points

  • 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.

Abstract

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.

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Figure 1: Transcriptional networks driving the GC reaction.
Figure 2: Origin of GC-derived lymphomas and the main oncogenic pathways.
Figure 3: Schematic representation of the pathways affected during lymphomagenesis in Burkitt lymphoma.
Figure 4: Schematic representation of the pathways affected during lymphomagenesis in follicular lymphoma.
Figure 5: Schematic representation of the pathways affected during lymphomagenesis in DLBCL.

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Acknowledgements

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.

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Correspondence to Riccardo Dalla-Favera.

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Glossary

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.

MicroRNAs

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.

CARD11–BCL-10–MALT1

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.

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Basso, K., Dalla-Favera, R. Germinal centres and B cell lymphomagenesis. Nat Rev Immunol 15, 172–184 (2015). https://doi.org/10.1038/nri3814

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