REVIEWS
`
`MECHANISMS OF B-CELL
`LYMPHOMA PATHOGENESIS
`
`Ralf Küppers
`
`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.
`
`In the Western world, about 20 new cases of lymphoma
`are diagnosed per 100,000 people per year1. About 95%
`of the lymphomas are of B-cell origin, the rest are T-cell
`malignancies. This might be surprising at first glance,
`given the similar frequency of B and T cells in the
`human body, but is understandable considering the spe-
`cific factors that influence the pathogenesis of B-cell
`lymphomas. About 15 types of B-cell lymphoma are
`distinguished in the current World Health Organization
`lymphoma classification2 (TABLE 1). The distinction of
`these lymphomas is not only relevant in terms of lym-
`phoma pathogenesis, but also regarding the conse-
`quences for treatment of the patients. This is because
`the various types of B-cell lymphoma can have very dif-
`ferent clinical behaviours, and therefore require diverse
`treatment strategies.
`Exciting progress has been made in the past 20
`years to elucidate the cellular origin of human B-cell
`lymphomas and the identification of key transforming
`events, in particular the role of chromosomal translo-
`cations in lymphoma pathogenesis. However, it is
`becoming clear that B-cell tumours are not as
`autonomous as previously thought — key factors that
`are crucial for normal B-cell differentiation and sur-
`vival are also required for the malignant growth of
`most B-cell lymphomas. What is the cellular origin of
`B-cell lymphomas and what are the main transform-
`ing events? How do antigen activation of the B-cell
`receptor (BCR) and the cellular microenvironment
`contribute to the pathogenesis of B-cell lymphomas?
`
`Cellular origin of B-cell lymphomas
`B-cell development takes place in distinct differentiation
`steps that are characterized by the specific structure of
`the BCR. The BCR is composed of two identical heavy-
`chain and two identical light-chain immunoglobulin
`(Ig) polypeptides that are covalently linked by disul-
`phide bridges. Other components of the BCR are the
`CD79A AND CD79B molecules, which contain cytoplasmic
`immunoreceptor tyrosine-based activation motifs.
`These motifs transmit signals following BCR crosslink-
`ing. The intracellular signalling components activated
`by BCR crosslinking include several tyrosine kinases.
`Depending on the differentiation stage of the B cell that
`recognizes an antigen and on the activation of other
`B-cell surface receptors that modulate BCR signalling,
`the activated B cell might be induced to proliferate
`and/or undergo further differentiation steps3.
`Early B-cell development, which occurs in the
`bone marrow, concludes when a B-cell precursor suc-
`cessfully rearranges Ig heavy- and light-chain genes
`and is equipped with a functional surface antigen
`receptor (FIG. 1). Cells that express a functional (and
`non-autoreactive) BCR differentiate into mature
`naive B cells and leave the bone marrow, whereas
`B-cell precursors that fail to express a BCR undergo
`apoptosis3. Mature naive B cells can be activated by
`antigen binding to the BCR and participate in
`immune responses. In T-cell-dependent immune
`responses, antigen-activated B cells undergo clonal
`expansion in structures called ‘germinal centres’
`
`CD79A AND CD79B
`Components of the B-cell
`receptor that mediate signalling
`following crosslinking.
`
`Institute for Cell Biology
`(Tumor Research),
`University of Duisburg-
`Essen, Medical School,
`Virchowstraße 173, 45122
`Essen, Germany.
`e-mail: ralf.kuppers@
`uni-essen.de
`doi:10.1038/nrc1589
`
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`R E V I E W S
`
`Summary
`
`• 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.
`
`(GCs), where the the Ig genes are modified by somatic
`hypermutation and class-switch recombination (FIGS 1,2).
`As distinct stages of B-cell development and differ-
`entiation are characterized by the particular structure of
`the BCR and expression patterns of differentiation
`markers, and as these processes often take place in spe-
`cific histological structures, analysis of these features
`was used to determine the origin of the various human
`B-cell lymphomas4,5 (TABLE 1). The rationale for such a
`classification of B-cell lymphomas is based on the
`observation that malignant B cells seem to be ‘frozen’ at
`a particular differentiation stage, which reflects their ori-
`gin4,6,7. One of the main concepts emerging from these
`studies is that most types of B-cell lymphoma are
`derived from GC or post-GC B cells4,5 (BOX 1).
`The cellular origin of B-cell lymphomas was further
`clarified, and previously unrecognized distinct lym-
`phoma subtypes were also identified, by gene-expression
`profiling of human B-cell lymphomas and normal B-cell
`subsets. Such studies identified, for example, a GC B-cell
`gene-expression signature that is associated with follicu-
`lar lymphoma, Burkitt’s lymphoma and a subset of dif-
`fuse large B-cell lymphomas8. These findings supported
`the GC B-cell origin of these tumours. Gene-expression
`profiling studies of other malignancies also revealed
`unexpected relationships, in terms of gene-expression
`patterns. For example, in addition to B-cell chronic lym-
`phocytic leukaemia (B-CLL) cells with mutated Ig vari-
`able (V)-region genes, B-CLL cells with unmutated Ig
`V-region genes showed greatest similarity to memory
`B cells that had undergone somatic hypermutation, indi-
`cating that both subtypes of B-CLL are related to mem-
`ory B cells9. Moreover, a subset of diffuse large B-cell
`lymphomas was identified that, among the various B-cell
`subsets included in the analysis, most closely resembled
`
`in-vitro-activated B cells8. In these cancer cells, the trans-
`formation process might have been associated with an
`alteration of the gene-expression profile, masking the sig-
`nature of the cell of origin, as seems to be the case in clas-
`sical Hodgkin’s lymphoma (see below). It is also possible
`that the normal B-cell counterpart of some cancer types
`might not have been identified yet. In the activated B-cell
`type of diffuse large B-cell lymphoma, the normal coun-
`terpart could be a poorly defined, small subset of GC B
`cells that is undergoing plasmacytoid differentiation, or a
`post-GC immunoblast population7.
`
`Transforming events
`Reciprocal chromosomal translocations involving one
`of the Ig loci and a proto-oncogene are a hallmark of
`many types of B-cell lymphoma10,11 (TABLE 2). As a con-
`sequence of such translocations, the oncogene comes
`under the control of the active Ig locus, causing a dereg-
`ulated, constitutive expression of the oncogene. Three
`types of breakpoints can be distinguished in the Ig loci.
`Some translocations, such as the BCL2–IgH transloca-
`tion associated with follicular lymphoma, have break-
`points that are directly adjacent to Ig heavy chain
`J-region (JH) gene segments or that are adjacent to
`regions where the Ig heavy chain D-region (DH) joins
`the J-region (DHJH) (FIG. 1). As the breakpoints also often
`show loss of nucleotides at the end of the JH or DH seg-
`ments and the addition of non-germline-encoded
`nucleotides — typical features of V(D)J recombination
`— it is likely that these translocations happen as mis-
`takes during V(D)J recombination in early B-cell devel-
`opment in the bone marrow12–14. In other translocations,
`the breakpoints are found within or adjacent to
`rearranged V(D)J genes, and these V-region genes are
`always somatically mutated. These and additional fea-
`tures indicate that such translocations occur as by-prod-
`ucts of the somatic hypermutation process10,15, which is
`associated with DNA strand breaks15–17. The third type of
`translocation is characterized by breakpoints in the IgH
`constant region switch regions, in which DNA breaks are
`introduced during class switching. This indicates that
`these events occur during class-switch recombination.
`The causes for the generation of DNA strand breaks
`in the oncogenes involved in Ig-associated transloca-
`tions are less clear10. Some of these genes, however,
`undergo aberrant somatic hypermutation, and there-
`fore acquire DNA strand breaks in the same regions
`where the chromosomal breakpoints are located (see
`below)18. Regarding the BCL2–IgH translocations asso-
`ciated with follicular lymphoma, it was recently shown
`that the DNA in the major breakpoint region of the BCL2
`gene often acquires an altered structure that is cut by the
`RAG nucleases, which mediate V(D)J recombination.
`This finding indicates that in these translocations, RAG-
`mediated DNA cleavage is responsible for the DNA
`breaks in both partners involved in the translocation19.
`RAG enzymes might also be involved in chromosomal
`translocations through another mechanism — RAGs
`have been shown to possess transposase activity, so some
`translocation events could be explained by double-ended
`transposition events20,21.
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`R E V I E W S
`
`Frequency among Proposed cellular origin
`lymphomas (%)*
`
`7
`
`5
`
`<1
`
`20
`
`<1
`
`7
`
`2
`
`1
`
`2
`
`Memory B cell? Naive B cell?
`Marginal-zone B cell?
`
`CD5+ mantle-zone B cell
`
`Memory B cell
`
`GC B cell
`
`Memory B cell
`
`Marginal-zone B cell
`
`Marginal-zone B cell?
`Monocytoid B cell?
`
`Subset of naive B cells that
`have partially differentiated
`into marginal-zone B cells?
`
`GC B cell
`
`30–40
`
`GC or post-GC B cell
`
`(Post) GC B cell
`
`(Post) GC B cell
`
`Plasma cell
`
`Defective GC B cell
`
`1
`
`10
`
`10
`
`0.5
`
`GC B cell
`
`Subtype of diffuse large B-cell lymphoma located in the mediastinum. 2
`Tumour cells are large B cells but also show a number of similarities
`to Reed–Sternberg cells of classical Hodgkin’s lymphoma. Most
`frequently occurs in young women.
`
`Thymic B cell
`
`Mostly of the diffuse large-cell lymphoma type.
`Lymphomas that arise in patients after organ transplantation.
`Immunosuppressive treatment confers risk of uncontrolled
`proliferation of EBV-infected B cells that can develop into
`lymphomas.
`
`<1
`
`GC B cell
`
`Frequently occurs in patients with AIDS or patients who have
`received organ transplants. Lymphoma cells are found as effusions in
`serous cavities, such as pleura, pericardium or peritoneum.
`
`<0.5
`
`Table 1 | Human mature B-cell lymphomas
`
`Lymphoma
`
`Features
`
`B-cell chronic lymphocytic Leukaemia of small B cells that express the CD5 antigen, involving
`leukaemia (B-CLL)
`peripheral-blood and bone-marrow cells. Common in elderly
`patients. Called ‘small lymphocytic lymphoma’ when lymph-node
`cells are predominantly involved. Patients with leukaemia cells that
`lack variable (V)-region gene mutations have a worse prognosis than
`patients with mutations in V-region genes.
`
`Lymphoma arises from cells that populate the mantle zone of
`follicles, express CD5 and show aberration in cyclin-D1 expression.
`Nearly all cases are associated with BCL1–IgH translocation.
`
`Chronic B-cell malignancy related to B-CLL. Over 50% of cancer
`cells represent prolymphocytes (large lymphocytes with clumped
`chromatin and prominent nucleolus).
`
`A nodal lymphoma with a follicular growth pattern. Lymphoma cells
`morphologically and phenotypically resemble GC B cells.
`Most cases are associated with BCL2–IgH translocation.
`
`Chronic B-cell malignancy involving spleen and bone marrow.
`Very few circulating leukaemia cells. Tumour cells form ‘hairy’
`projections.
`
`Extranodal marginal-zone B-cell lymphoma. Develops mostly in
`aquired lymphoid structures.
`
`Lymphoma with primary presentation in lymph nodes.
`Lymphoma cells resemble marginal-zone or monocytoid B cells, but
`often have heterogenous cytology, which ranges from small to large
`lymphocytes and includes plasma cells.
`
`Micronodular lymphoid infiltration in the splenic white pulp. Mostly
`small IgD+ lymphoma cells that replace normal follicles and the
`marginal-zone region. Frequently involves infiltration into bone
`marrow and circulation.
`
`Fast growing. Mostly extranodal. Characterized by a MYC–Ig
`translocation. Patients with endemic form are EBV-positive in nearly
`all cases. Patients with sporadic form are EBV-positive in about 30%
`of cases.
`
`Heterogenous group of lymphomas characterized by large B cells.
`Several subtypes are recognized. Morphological variants include
`centroblasts and immunoblasts.
`
`Mantle-cell lymphoma
`
`B-cell prolymphocytic
`leukaemia
`
`Follicular lymphoma
`
`Hairy-cell leukaemia
`
`MALT lymphoma
`
`Nodal marginal-zone
`lymphoma
`
`Splenic marginal-zone
`lymphoma
`
`Burkitt’s lymphoma
`
`Diffuse large B-cell
`lymphoma
`
`Primary mediastinal
`B-cell lymphoma
`
`Post-transplant
`lymphoma
`
`Primary effusion
`lymphoma
`
`Lymphoplasmacytic
`lymphoma
`
`Involves lymph nodes, bone marrow and spleen.
`The tumour-cell population is composed of small B
`cells, plasmacytoid lymphocytes and plasma cells.
`Most patients present with a serum monoclonal
`protein, usually of the IgM type.
`
`Multiple myeloma
`
`Neoplastic proliferation of plasma cells in the bone marrow.
`
`Classical Hodgkin’s
`lymphoma
`
`Characterized by bizarre, large tumour cells. Hodgkin and
`Reed–Sternberg cells account for less than 1% of cells in the tumour,
`and are admixed with various non-neoplastic cell types. Tumour
`cells show a phenotype not characteristic of any normal
`haematopoietic cell type.
`
`Lymphocyte-predominant Rare indolent subtype of Hodgkin’s lymphoma.
`Hodgkin’s lymphoma
`Lymphoma cells show a B-cell phenotype, represent a small
`population in the tissue, and grow in association with follicular
`dendritic cells and T-helper cells.
`Good prognosis.
`
`*These numbers refer to the frequencies in Europe and North America. AIDS, acquired immune deficiency syndrome; EBV, Epstein–Barr virus; Ig, immunoglobulin; MALT,
`mucosa-associated lymphoid tissue; GC, germinal centre.
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`R E V I E W S
`
`CD95
`Cell-surface receptor that
`mediates apoptosis signalling.
`
`a VDJ recombination
`
`b Somatic hypermutation
`
`c Class switch
`
`VH
`
`VH
`
`DH
`
`JH
`
`JH
`
`Cµ
`
`VH
`
`Sµ
`
`Cµ
`
`VH
`
`Sµ
`
`Cµ
`
`Cδ
`
`Sγ1
`
`Cγ1
`
`VH
`
`VH
`
`DH JH
`
`Cµ
`
`X X X
`
`Sµ
`
`Cµ
`
`VH
`
`Sµ Sγ1
`
`Cγ1
`
`VH DH JH
`
`Cµ
`
`Figure 1 | Molecular processes that remodel immunoglobulin genes. Immunoglobulins (Igs) are expressed by B cells and
`consist of variable (V) regions, which interact with antigen, and constant (C) regions, which mediate the effector functions of Igs. To
`create a functional Ig, B cells must rearrange DNA segments that encode the heavy (H)- and light-chain (not shown) regions of the
`variable genes. a | First, through a process called ‘V(D)J recombination’, three gene segments, VH, DH and JH, are joined to encode the
`H-chain variable region. The V regions of the κ- and λ-light chains, alternatively, are each encoded by two gene segments — the VL
`and JL genes (not shown). B-cell precursors first carry out DH–JH rearrangements in H-chain genes. These DH–JH rearrangements are
`followed by VH–DHJH rearrangements, resulting in the expression of a pre-B-cell receptor if the rearrangement is productive3. About 50
`functional VH gene segments, 27 DH segments and 6 JH segments are available in the germline, allowing the generation of a diverse
`repertoire of VH gene rearrangements. The diversity is further increased by the addition or removal of nucleotides at the joining sites of
`the gene segments3. The cells then carry out rearrangements at their L-chain loci (not shown). The V-region of the Ig gene is ultimately
`connected to the C-region of the Ig gene (Cµ of IgM in diagram) b | The process of somatic hypermutation is activated when B cells
`reach the germinal centre (GC, shown in more details in FIG. 2). This process leads to the introduction of point mutations, deletions or
`duplications in the rearranged V-region of Ig genes (denoted by ‘Xs’ in the figure)102. These mutations occur in the V-region of Ig genes
`— not in the downstream Cµ region. c | Class switching results in the replacement of the originally expressed H-chain C-region gene
`with that of another Ig gene. In the diagram, the C-region for IgM (Cµ) and IgD (Cδ) are exchanged for the C-region of IgG (Cγ1) by
`recombination at the switch regions for these genes (Sµ and Sγ1, respectively). This results in an antibody with different effector
`functions but the same antigen-binding domain.
`
`The process of somatic hypermutation contributes
`to lymphoma pathogenesis not only by causing chro-
`mosomal translocations, but probably also by targeting
`non-Ig genes. Two situations have to be distinguished.
`The genes encoding BCL6 and CD95 (also known as FAS)
`were found to contain mutations in a considerable frac-
`tion of normal GC and memory B cells, indicating that
`these genes are often targeted by the hypermutation
`machinery in normal B cells22–24. In rare instances, such
`mutations might promote the development of lym-
`phomas. For example, inactivating mutations of CD95
`are found in about 20% of (post) GC B-cell lymphomas
`and could protect lymphoma cells from death induction
`by CD95-ligand-expressing cells25. In the case of the
`BCL6 gene, the frequent occurrence of hypermutation
`might also cause translocations of this gene into Ig- as
`well as non-Ig-encoding loci. This possibility was indi-
`cated by the finding that the 5′ region of BCL6, which
`is the site of hypermutation, is also the region where
`chromosomal-translocation breakpoints are mostly
`found18,23. In diffuse large B-cell lymphomas, aberrant
`hypermutation of multiple oncogenes has been
`reported, which might also represent an important
`mechanism of pathogenesis18.
`Two of the molecular processes that could cause chro-
`mosome translocations or mutations in non-Ig genes
`occur exclusively (or at least mainly) in the GC —
`somatic hypermutation and class-switch recombination26 .
`This could be one of the reasons that most B-cell lym-
`phomas derive from GC B cells or their descendents.
`Class switching and somatic hypermutation do not
`occur in the DNA of T cells, which could also partly
`explain why B cells are more prone to undergo malignant
`transformation than T cells.
`
`Whereas chromosome translocations involving Ig
`loci are clearly a hallmark of many types of B-cell lym-
`phoma, many other transforming events have also been
`implicated in the pathogenesis of lymphomas, such as
`mutations in tumour-suppressor genes (such as TP53
`and the gene encoding IκBα), genomic amplifications
`(such as REL) and translocations not involving Ig loci
`(API2–MALT1) (TABLE 2).
`Finally, viruses might also be involved in the trans-
`formation of B cells. The most well-known example is
`Epstein–Barr virus (EBV), which is found in nearly all
`endemic Burkitt’s lymphomas, in many post-trans-
`plant and primary effusion lymphomas, and in about
`40% of cases of classical Hodgkin’s lymphoma (see
`REFS 27–30 for reviews) (TABLE 2). Another member of
`the herpes-virus family, human herpes virus 8, is
`implicated in the pathogenesis of primary effusion
`lymphomas31. The oncogenic features of herpes virus 8
`are not well understood, but it was recently shown
`that the viral protein FLIP activates the transcription
`factor NF-κB, which is an important survival factor in
`primary effusion lymphoma cells32.
`
`Role of the BCR in B-cell lymphomas
`Role of the BCR in the survival of normal B cells.
`Throughout their lives, B cells undergo stringent selec-
`tion for expression of the appropriate BCR. Pre-B cells
`are selected for a pre-BCR (composed of Ig heavy chains
`and surrogate light chains), and immature B cells are
`selected for expression of a non-autoreactive, functional
`BCR. After these steps, GC B cells are only able to survive
`the GC reaction and differentiate into memory or
`plasma cells if somatic mutations in their V-region genes
`result in expression of a BCR with increased affinity for a
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`Mantle zone
`
`Class switching
`
`Mutations that
`increase
`antigen affinity
`
`FDC
`
`Light zone
`
`Selection
`
`T cell
`
`Differentiation
`
`Mutations that
`reduce antigen
`affinity
`
`R E V I E W S
`
`Plasma cell
`
`Memory B cell
`
`V-region gene
`recombination
`
`Somatic
`hypermutation
`
`Clonal expansion
`
`B-cell
`precursor
`
`Naive B cell
`
`Dark zone
`
`No BCR
`
`B cell
`
`Apoptosis
`
`Figure 2 | B-cell differentiation in the germinal-centre reaction. Mature (naive) antigen-activated B cells that receive signals
`known as ‘T-cell help’ are driven into primary B-cell follicles in secondary lymphoid organs such as lymph nodes, where they
`establish germinal centres (GCs; lightest yellow region) 103. The naive IgM+IgD+ B cells that constitute the primary B-cell follicle are
`replaced by the proliferating GC B cells and displaced to the outside of the follicle, where they form a mantle zone around the GC. In
`the GC, a dark zone and a light zone can be distinguished (left and right sides, respectively). The dark zone mainly consists of
`proliferating GC B cells, whereas the GC B cells in the light zone are resting103. In proliferating GC B cells, the process of somatic
`hypermutation is activated, which leads to the introduction of mutations at a high rate into the rearranged Ig variable (V)-region genes
`of the B cells102. Most mutations are disadvantagous for the cells— such as those that lead to reduced affinity of the BCR for antigen
`and cause cells to undergo apoptosis. A few GC B cells will acquire mutations in the BCR that increase their affinity for antigen, and
`these cells will be positively selected. The selection process presumably takes mainly place in the light zone, where the GC B cells are in
`close contact with CD4+ T cells and follicular dendritic cells (FDCs). A fraction of these GC B cells undergo class-switch
`recombination104. Finally, GC B cells differentiate into memory B cells or plasma cells and leave the GC microenvironment.
`
`cognate antigen3. Even mature resting B cells are con-
`stantly under selective pressure to express the BCR —
`ablation of BCR expression in mice leads to the apoptotic
`death of BCR-negative B cells33,34. So, it seems that this
`BCR dependency is a main determinant of B-cell sur-
`vival. It is still debated whether the survival signal sup-
`plied by the BCR is an autonomous signal or is initiated
`by low-level BCR activation by antigen.
`
`BCR dependency of B-cell lymphomas. The selection for
`expression of a BCR also seems to occur in malignant B
`cells. Indeed, most B-cell lymphomas still express a BCR,
`although sometimes at relatively low levels35–37 (BOX 2).
`The proposal that there is a need for BCR-derived sur-
`vival signals is indirectly supported by the observation
`that translocations into the Ig-loci are virtually always
`found on the non-productively rearranged Ig loci, with a
`few exceptions38. As the three Ig-gene-remodelling
`processes that are implicated in the generation of these
`translocations — V-region gene recombination, class
`switching and somatic hypermutation (FIG. 1) — princi-
`pally occur in both Ig alleles, translocation events should
`happen at nearly equal frequency on the expressed Ig
`allele and the non-expressed allele. However, as the
`expressed Ig alleles are not found to be inactivated by
`translocation events, it seems that at least at the time
`that the translocations happened, the inability to form a
`BCR was incompatible with survival of the cells and
`development into a B-cell tumour.
`
`Further evidence that the BCR supplies important
`survival signals to B-cell lymphoma cells is provided by
`the observation that treatment of patients who have fol-
`licular lymphoma with ANTI-IDIOTYPIC ANTIBODIES did not
`result in the emergence of BCR-negative lymphoma
`variants — either through downregulation of BCR
`expression or by selected outgrowth of clones with inac-
`tivating Ig V-region gene mutations39,40. Finally, several
`types of lymphoma show ongoing V-region gene muta-
`tion during tumour clone expansion39,41–44. As a consid-
`erable fraction of mutations would interfere with BCR
`expression or function, such as nonsense mutations or
`replacement mutations that prevent proper heavy- and
`light-chain pairing, it is notable that such lymphomas
`also retain BCR expression35,37. Indeed, it has been deter-
`mined that two types of destructive somatic mutation
`— nonsense mutations and deletions or duplications
`causing reading-frame shifts — account for nearly 10%
`of mutation events, if mutations accumulate under
`non-selective conditions15,45. So, the rare occurence
`of BCR-loss variants of lymphomas with ongoing
`somatic hypermutation, such as follicular lymphoma,
`Burkitt’s lymphoma,
`lymphocyte-predominant
`Hodgkin’s lymphoma or mucosa-associated lym-
`phoid tissue (MALT) lymphomas, is a strong indica-
`tion that lymphoma cells undergo selection for BCR
`expression. Therefore, the survival signals supplied by
`BCR expression in normal B cells might also promote
`survival of B-cell lymphoma cells.
`
`ANTI-IDIOTYPIC ANTIBODIES
`Antibodies that bind to the
`unique determinants in the
`V-region of another antibody.
`
`NATURE REVIEWS | C ANCE R
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`Exceptional B-cell lymphomas that do not express the
`BCR. Although evidence is strong that most B-cell lym-
`phomas depend on BCR expression, there are a few
`exceptions (BOX 2). In classical Hodgkin’s lymphoma,
`inactivating Ig V-region gene mutations that render
`
`originally functional V-region gene rearrangements
`non-functional were detected in 25% of cases46,47. As
`only a small fraction of inactivating mutations that
`occur in mutating GC B cells can easily be identified
`(for example, nonsense mutations and deletions), it is
`
`Box 1 | Cellular origin of human B-cell lymphomas
`
`Human B-cell lymphomas are assigned to their proposed normal B-cell counterpart. Most lymphomas are derived from
`germinal-centre (GC) B cells or from B cells that have passed through the GC, indicating its role in the pathogenesis of
`B-cell lymphoma. As shown in the figure, the GC is surrounded by a mantle zone of naive B cells, most of which express
`the CD5 marker — these might comprise a distinct B-cell subset. The marginal zone is a B-cell-rich zone located between
`B-cell follicles and the T-cell area in the spleen (a similar region is present in Peyer’s patches, but usually not in lymph
`nodes). The origin of marginal-zone B cells is debated, and probably includes post-GC memory B cells and naive B cells
`involved in T-cell-independent immune responses. Extranodal mucosa-associated lymphoid tissue (MALT) lymphomas
`and nodal marginal-zone B-cell lymphomas (not shown) are presumably derived from marginal-zone B cells. Splenic
`marginal-zone B-cell lymphomas comprise both follicular and marginal-zone B cells, and often carry unmutated
`variable (V)-region genes. These lymphomas might therefore be derived from naive B cells prone to undergo marginal-
`zone B-cell differentiation105. Whereas most mantle-cell lymphomas are believed to be derived from CD5+ (naive) B cells
`of the mantle zone, about 20–30% of cases carry mutated V-region genes, indicating that they have passed through the
`GC. The origin of B-cell chronic lymphocytic leukaemia (B-CLL) cells has been debated. About half of the cases of B-
`CLL carry mutations in V-region genes. Both subsets of B-CLL have been proposed to derive either from CD5+ B cells,
`memory B cells or marginal-zone B cells106. Post-transplant lymphomas, which often develop in patients after organ
`transplantation, are often derived from antigen-selected, BCR-expressing GC B cells, whereas others might be derived
`from pre-apoptotic GC B cells55–57. Gene-expression profiling identified two main subtypes of diffuse large B-cell
`lymphoma (DLBCL), one with a profile resembling GC B cells (GC-type), and the other resembling in-vitro-activated
`B cells (ABC-type)8. Primary mediastinal B-cell lymphomas are believed to be derived from post-GC B cells of the thymus.
`Solid arrows denote B-cell differentiation steps and broken arrows assign the various lymphomas to their proposed
`normal counterpart.
`
`DLBCL (ABC-type)
`Primary mediastinal
`B-cell lymphoma
`
`Memory B cell
`
`Hairy-cell leukaemia
`Prolymphocytic leukaemia
`
`Splenic marginal-
`zone lymphoma
`
`Marginal zone
`
`Germinal centre
`
`B-CLL
`
`MALT lymphoma
`
`Multiple myeloma
`
`Naive B cell
`
`GC
`B cell
`
`Mantle
`zone
`
`Plasmablast
`
`Plasma
`cell
`
`B-CLL
`(unmutated V gene)
`
`Lymphoplasmacytic lymphoma
`Primary effusion lymphoma
`
`Mantle-cell lymphoma
`B-CLL (unmutated V-region genes)
`
`CD5
`A cell-surface glycoprotein that
`is expressed by virtually all
`T cells and a subset of B cells.
`
`Follicular lymphoma
`Burkitt's lymphoma
`DLBCL (GC-type)
`Lymphocyte-predominant
`Hodgkin's lymphoma
`
`Classical Hodgkin's
`lymphoma
`
`Post-transplant
`lymphomas
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`possible that Hodgkin and Reed–Sternberg (HRS)
`cells — the tumour cells in patients with classical
`Hodgkin’s lymphoma — in most if not all cases are
`derived from pre-apoptotic GC B cells that have lost
`the capacity to express high-affinity BCR. How can
`HRS cells escape selection to evade apoptosis? In
`about 40% of cases of classical Hodgkin’s lymphoma,
`HRS cells are infected by EBV and express the EBV-
`encoded latent membrane protein 2A (LMP2A)28.
`LMP2A harbours an immunoreceptor tyrosine-based
`activation motif, which is also found in the CD79A
`and CD79B (also known as Igα and Igβ, respectively)
`molecules of the BCR and is required for BCR-medi-
`ated survival signalling33. Studies of transgenic mice
`that express LMP2A in B cells have shown that
`LMP2A expression can replace the BCR-mediated sig-
`nals48,49. So, expression of LMP2A in an EBV-infected
`GC B cell that is undergoing hypermutation might
`rescue the cell from apoptosis following acquisition of
`unfavourable somatic V-region gene mutations. After
`acquisition of additional transforming events (other
`
`than EBV infection), that cell could, in rare instances,
`give rise to an HRS tumour clone46. The role of
`LMP2A in the established HRS cell clone, however, is
`less clear, because HRS cells have downregulated
`expression of central components of the BCR sig-
`nalling cascade50, including spleen tyrosine kinase
`(SYK) and SLP65, which seem to be essential for the
`function of LMP2A as a BCR surrogate51,52.
`Indeed, HRS cells have lost expression of nearly all
`B-cell-typical genes50,53,54. Whether this ‘lost B-cell phe-
`notype’ is directly related to pathogenesis and/or the
`presumed derivation from crippled GC B cells is
`unclear. Perhaps, for a GC B cell, which because of dis-
`advantageous somatic mutations does not receive
`appropriate survival signals and would therefore nor-
`mally undergo apoptosis, it is advantageous to lose its
`B-cell identity as a means of becoming independent
`from the stringent selection for expression of a (high-
`affi