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Mechanisms of B-cell lymphoma pathogenesis

Key Points

  • A hallmark of many types of B-cell lymphoma is reciprocal chromosomal translocations involving one of the immunoglobulin loci and a proto-oncogene. As a consequence of such translocations, the oncogene comes under the control of an active immunoglobulin locus, causing deregulated, constitutive expression of the translocated gene.

  • Normal B cells depend on B-cell receptor (BCR) expression for survival. The selection for expression of a BCR also seems to operate in most malignant B cells.

  • Although there is strong evidence that most B-cell lymphomas depend on BCR expression, there are a few exceptions — namely classical Hodgkin's lymphoma, primary mediastinal B-cell lymphoma, some post-transplant lymphomas, and the rare primary effusion lymphomas.

  • In several lymphomas, there is a strong indication that the lymphoma cells recognize an antigen and that stimulation by antigen binding contributes to the survival and proliferation of lymphoma cells.

  • In many lymphomas, such as follicular lymphoma, mucosa-associated lymphoid tissue lymphomas and classical Hodgkin's lymphoma, the tumour microenvironment seems to be important for the survival and/or proliferation of the lymphoma cells.

  • The recognition that the survival and/or proliferation of many B-cell lymphomas depends on their interaction with other cells in the microenvironment, as well as on expression of the B-cell receptor and, sometimes, antigen activation, might lead to novel treatment options for B-cell lymphomas.

Abstract

Chromosomal translocations involving the immunoglobulin loci are a hallmark of many types of B-cell lymphoma. Other factors, however, also have important roles in the pathogenesis of B-cell malignancies. Most B-cell lymphomas depend on the expression of a B-cell receptor (BCR) for survival, and in several B-cell malignancies antigen activation of lymphoma cells through BCR signalling seems to be an important factor for lymphoma pathogenesis. Recent insights into the lymphomagenic role of factors supplied by the microenvironment also offer new therapeutic strategies.

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Figure 1: Molecular processes that remodel immunoglobulin genes.
Figure 2: B-cell differentiation in the germinal-centre reaction.

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Acknowledgements

I am grateful to the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe, M. S. Stiftung and the IFORES program of the University of Essen Medical School for support. I thank K. Rajewsky for critical comments on the manuscript.

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DATABASES

Entrez Gene

API2

BCL2

BCL6

BOB1

CD40

CD79A

CD79B

CD95

IgH

IκBα

MALT1

OCT2

PU.1

REL

TARC

TP53

National Cancer Institute

Hodgkin's lymphoma

multiple myeloma

OMIM

autoimmune lymphoproliferative disease

rheumatoid arthritis

Sjogren's syndrome

FURTHER INFORMATION

Lymphoma/Leukemia Molecular Profiling Project

Glossary

CD79A AND CD79B

Components of the B-cell receptor that mediate signalling following crosslinking.

CD95

Cell-surface receptor that mediates apoptosis signalling.

ANTI-IDIOTYPIC ANTIBODIES

Antibodies that bind to the unique determinants in the V-region of another antibody.

CD5

A cell-surface glycoprotein that is expressed by virtually all T cells and a subset of B cells.

CD19

B-cell-specific surface molecule expressed from the earliest B-cell precursor stages up to the plasmablast stage. Regulates the responsiveness of B cells following B-cell-receptor crosslinking.

CD20

B-cell-specific surface marker expressed by pre-B and all mature B cells. Downregulated on plasma cells.

AUTOANTIGEN

A component of the body that is recognized by antibodies of the individual's own B cells.

ANTIGENIC EPITOPES

Sites on an antigen that are recognized by an antibody.

SUPERANTIGEN

Binds to conserved region of the the B-cell receptor, and therefore stimulates many B cells.

CD4

Co-receptor for major histocompatitibility complex class II on T-helper cells.

CD40

Receptor for co-stimulatory signals for B cells.

CD40L

Ligand for CD40, expressed on T cells.

CD80

Co-stimulatory molecule expressed on B cells. Interacts with ligands expressed by T cells.

CD86

Co-stimulatory molecule mainly expressed on activated B cells. Interacts with ligands expressed by T cells.

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Küppers, R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer 5, 251–262 (2005). https://doi.org/10.1038/nrc1589

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