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LYMPHOID BIOLOGY AND DISEASES: Edited by Ari M. Melnick

Unexpected functions of nuclear factor-κB during germinal center B-cell development

implications for lymphomagenesis

Klein, Ulfa,b,c; Heise, Nicolec

Author Information
Current Opinion in Hematology: July 2015 - Volume 22 - Issue 4 - p 379-387
doi: 10.1097/MOH.0000000000000160
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Abstract

INTRODUCTION

The hallmark of T-cell-dependent antibody responses is the generation of high-affinity memory B cells and plasma cells during the germinal center reaction. The germinal center reaction is essential for our immunity against invading microorganisms; however, this reaction is inherently dangerous, as suggested by the observation that the majority of human B-cell malignancies originate from the transformation of antigen-experienced B cells that have undergone the germinal center reaction [1,2].

Box 1
Box 1:
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The germinal center reaction

Germinal centers are specialized microenvironments that form upon T-dependent activation of antigen-specific B cells within lymph nodes or spleen [3,4]. A mature germinal center comprises two functionally distinct compartments, a dark zone and a light zone [5,6]. Dark zone B cells undergo rapid proliferation during which their antibody genes are modified by activation-induced cytidine deaminase (AID)-mediated immunoglobulin variable region (IgV) gene somatic hypermutation to generate a repertoire of antibody mutants with varying affinities to the immunizing antigen. Those with improved affinity to the antigen are positively selected in the light zone, where the cells may also undergo AID-mediated class switch recombination. Selected B cells can recirculate to the dark zone to undergo additional rounds of hypermutation and affinity selection, or they are instructed to differentiate into memory B cells or plasma cells and exit the germinal center.

Germinal center reaction and lymphomagenesis

Occasional errors during the AID-mediated, DNA-modifying processes of IgV hypermutation and class switch recombination can cause genetic alterations in germinal center B cells, leading to the deregulated or ectopic expression of oncogenes or the inactivation of tumor suppressor genes [7]. Importantly, it has emerged that the vast majority of genetic aberrations target genes with essential functions during germinal center B-cell development, such as MYC, BCL2, BCL6, and PRDM1 (encoding BLIMP1) [8,9]. As a result, the deregulated expression or inactivation of those genes disturbs the normal physiology of the germinal center reaction by exerting pro-survival or pro-proliferative effects, or by inhibiting the differentiation into post-germinal center memory B cells and plasma cells. To better understand how oncogenes or tumor suppressors contribute to germinal center lymphomagenesis, it is important to identify the functions of these genes during normal germinal center B-cell development. The recent finding that deregulated activity of nuclear factor-κB (NF-κB) is a major contributor to the pathogenesis of various germinal center-derived B-cell malignancies underscores the need to dissect the function of the complex NF-κB pathway in germinal center B-cell development.

The nuclear factor-κB pathway

NF-κB transcription factors are associated with controlling the expression of genes involved in cell survival, growth, stress responses, and inflammation in a cell-type or context-dependent fashion [10,11]. The five different NF-κB subunits c-REL, RELA, RELB, p50, and p52 occur as heterodimers or homodimers (p50 and p52 are generated by proteolytic cleavage from their precursors p105 and p100, respectively). Only the c-REL, RELA, and RELB subunits can drive transcription through transactivation domains. Upon activation, the dimers translocate from the cytoplasm to the nucleus, where they activate transcription of hundreds of target genes. Functionally, NF-κB transcription factors form two groups (Fig. 1). RELA, c-REL, and p50 comprise the subunits of the canonical NF-κB pathway that in B cells is mainly activated in response to stimulation through the antigen and Toll-like receptors and CD40 ligation [12,13]. The major heterodimers are RELA/p50 and c-REL/p50 (Fig. 1). RELB and p52 comprise the factors of the alternative pathway that in B cells is activated by CD40 ligation or BAFF [12,13] and occur as heterodimers.

FIGURE 1
FIGURE 1:
Nuclear factor (NF)-κB signaling pathway. NF-κB is a complex signaling cascade that comprises two separate pathways. The canonical pathway (left) is activated via signals through a range of cell surface receptors, most importantly the B-cell receptor (BCR) and CD40. The activation results in the inactivation of IκB, thereby releasing the heterodimers formed by the canonical NF-κB subunits RELA, c-REL, and p50 to translocate into the nucleus and to activate transcription of target genes. The alternative pathway (right) is activated by a more limited set of signals, including CD40. Proteasomal degradation of the precursor protein p100 results in the generation of the major heterodimer of the alternative pathway RELB/p52, which can then enter the nucleus and activate transcription of target genes. Only RELA, RELB, and c-REL can drive transcription of target genes because of transactivation domains.

ABERRANT ACTIVATION OF NUCLEAR FACTOR-κB IN B-CELL MALIGNANCIES

Constitutive NF-κB activity occurs in several B-cell-derived malignancies [9,14–19]. NF-κB can be activated by the tumor microenvironment [20] or as a result of infection with tumor viruses such as Epstein–Barr virus or Karposi's sarcoma-associated herpesvirus [21]. Recently, it emerged that a large percentage of Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma cases show constitutive NF-κB signaling as the result of genetic alterations in NF-κB pathway components [9,22–32] (Fig. 2). Importantly, the inhibition of abnormal NF-κB responses has effectively suppressed tumorigenesis in in-vitro and in-vivo assays [22–24], consistent with the demonstration of an oncogenic role for NF-κB in mice [33].

FIGURE 2
FIGURE 2:
Multiple mutations in nuclear factor (NF)-κB pathway components can constitutively activate the canonical or alternative pathway. Summary of genetic mutations in NF-κB pathway components that result in the constitutive activation of the canonical or alternative pathway (see text). Genes in which mutations leading to constitutive activation of NF-κB were identified are marked with an asterisk.

Mutations have been identified in NF-κB pathway components, which lead to the preferential activation of either the canonical or the alternative pathway. Particular tumor subtypes seem to be associated with an activation of particular NF-κB pathways, although this distinction is not absolute. The vast majority of cases of activated B-cell-type (ABC)-diffuse large B-cell lymphoma (DLBCL), the more aggressive subtype of DLBCL, carry genetic mutations, which lead to the activation of the canonical pathway [9,22–24]; only ∼10% of mutations are associated with aberrantly activating the alternative pathway [34–36], although the percentage of cases with nuclear p52 is higher [23], suggesting a broader role for this pathway. Also Hodgkin lymphoma shows predominantly mutations leading to the activation of the canonical pathway [25,32], with a subset of Hodgkin lymphoma harboring mutations in components of the alternative pathway [37,38]. Splenic marginal zone lymphoma harbors genetic aberrations that activate the canonical or alternative pathway at almost equal fractions [39]. Interestingly, a recent study reports that a fraction of mantle cell lymphoma cases that were insensitive to the treatment of inhibitors of the canonical pathway showed genetic aberrations in regulators of the alternative pathway and were susceptible to pharmacologic downmodulation of this pathway [40▪]. Although most mutations in multiple myeloma occur in upstream components associated with inducing the alternative pathway [27–29], it has been established that in this malignancy of transformed plasma cells, both NF-κB pathways are activated in the majority of cases [27,29,41]. Certain lymphoma subtypes including germinal center B-cell-type-DLBCLs, Hodgkin lymphoma, and mediastinal large B-cell lymphoma (MLBCL) show amplification of the REL (c-REL) locus [17,42–44]. It has been noted that Hodgkin lymphoma and MLBCL are associated with predominant nuclear translocation of c-REL [15–17], suggesting unique functions for single canonical NF-κB subunits in the pathogenesis of different lymphoma subtypes. Finally, chronic lymphocytic leukemia (CLL) tumor cells show activation of the canonical route [20,45], which is thought to be because of chronic antigen-stimulation of the B-cell receptor [46] and stimulation of CLL cells mediated by the tumor environment [20]. Recurrent mutations were identified in a negative regulator of the alternative NF-κB pathway in about ∼10% of CLL cases [47] and in two components of the canonical pathway at a similar rate [48,49,50▪].

In summary, aberrant NF-κB activation has been linked to the pathogenesis of many B-cell-derived malignancies, and the picture emerges that the canonical or alternative pathways, and potentially the separate NF-κB subunits, have specific roles in the oncogenic process. This specificity may be exploited for the development of targeted antitumor therapies, thus reducing systemic side-effects of ubiquitous NF-κB inhibition. An important step toward this goal is to understand the function of NF-κB in the tumor precursor cells.

NUCLEAR FACTOR-κB TRANSCRIPTION FACTORS IN GERMINAL CENTER B-CELL DEVELOPMENT

Although the roles of NF-κB in early B-cell development and naïve B-cell survival are well defined [12,13], the precise function of the separate NF-κB pathways and their subunits during the germinal center reaction and the differentiation into memory or plasma cells is less clear. Although NF-κB is known to be required during the initial antigen-dependent B-cell activation phase [12,13], which leads to germinal center formation, gene expression profiling analyses, and immunohistochemistry studies in the human revealed that the vast majority of germinal center B cells, that is dark zone and most light zone B cells, are not subjected to NF-κB signaling [51–53]. However, NF-κB is activated in a subset of light zone B cells presumably by stimulation of the B-cell receptor and the CD40-signaling pathway resulting in nuclear translocation of the canonical NF-κB subunits [52] (and likely also of the alternative subunits as CD40 is a strong activator of this pathway). Together, this indicates that NF-κB follows a biphasic activation pattern in B cells during the germinal center reaction, which prevented the study of the role of NF-κB transcription factors in germinal center B cells using constitutional knockout mice. Recently, the development of mouse models for conditional inactivation of NF-κB transcription factors has allowed to investigate this issue. We here focus on recent results from the analysis of the canonical NF-κB subunits c-REL and RELA in germinal center B-cell development.

c-REL IS REQUIRED FOR THE MAINTENANCE OF THE GERMINAL CENTER REACTION

Rel (encoding c-REL) constitutional knockout mice generate a normal mature B-cell repertoire [54–56], indicating that c-REL is not required for the maintenance of naïve B cells, or that this subunit is functionally redundant with RELA. However, in-vitro stimulation experiments clearly documented a role for c-REL during B-cell activation [54–57]. In accordance, c-REL-deficient mice are impaired in the formation of germinal centers upon T-dependent immunization [56,58] in a B-cell-intrinsic fashion (own unpublished observations). The question of how deletion of rel in the small subset of light zone B cells that exhibit nuclear translocation of c-REL affects germinal center development was addressed by crossing a conditional rel allele to mice that express the Cre-recombinase in germinal center B cells. These experiments revealed that deletion of rel in germinal center B cells led to the gradual collapse of mature germinal centers until the structure almost completely disappeared several days later [59▪]. The observation that both dark zone and light zone B cells disappeared at equal fractions suggests that c-REL is essential for the maintenance of the mature germinal center by controlling the cyclic reentry of antigen-selected light zone B cells back to the dark zone.

The germinal center collapse observed upon deletion of rel in germinal center B cells could not be rescued by constitutive antiapoptotic stimuli via a bcl2-transgene [59▪], indicating that prevention of apoptosis is unlikely to be c-REL's major function during selection in the germinal center. Instead, gene expression profile analysis indicated that rel-deleted germinal center B cells lacked the expression of a metabolic program that enables cell growth by providing the increased demands of rapidly cycling cells for energy and building blocks for anabolic reactions [59▪]. In accordance with these findings, in vitro-stimulated c-REL-deficient B cells failed to upregulate a metabolic program, were characterized by strongly impaired metabolic functions as measured by extracellular flux assays, and had a smaller cell size compared to c-REL-proficient B cells [59▪]. It therefore seems that c-REL's primary role in light zone B cells may be the establishment of a transcriptional program that mediates cell growth through facilitating enhanced biosynthesis of DNA, protein, and lipids. These findings add c-REL to a growing list of transcription factors that over the last few years have been found to be involved in the control of metabolic reprogramming during the differentiation of activated lymphocytes [60–63], and provide an additional example for the emerging role of NF-κB transcription factors in the regulation of metabolic processes [64,65].

The gradual disappearance of germinal centers upon rel deletion is strikingly reminiscent of the germinal center collapse observed upon functional inactivation of the c-MYC proto-oncogene in mature germinal centers [66,67]. It therefore seems that both transcription factors are required for sustaining the germinal center reaction by instructing positively selected B cells to recycle from the light zone back to the dark zone. The interplay between c-REL and c-MYC in the light zone B cells is currently unclear. A NF-κB signature is present in c-MYC+ light zone B cells [66], and vice versa, c-REL-deficient B cells lack a c-MYC signature [59▪], suggesting that both transcription factors are active in the same light zone B cells. Although c-MYC can be an NF-κB target gene [64], it seems unlikely that c-REL exerts its function in light zone B cells solely through the control of c-MYC. Rather, c-MYC and c-REL may jointly regulate a particular set of target genes in addition to their specific transcriptional targets. Future work is needed to dissect the relation between c-MYC and c-REL in germinal center B-cell development.

RELA IS REQUIRED FOR THE GENERATION OF GERMINAL CENTER-DERIVED PLASMA CELLS

Mainly because of the embryonic lethality observed upon constitutional rela deletion [68], relatively little is known about the role of the canonical NF-κB subunit RELA in mature B-cell development. Evidence suggests that, similar to c-REL, RELA is not required for the generation of a normal mature B-cell repertoire [69]. However, data obtained from the study of conditional knockout mice suggest that RELA and c-REL play distinct roles during the germinal center reaction. Specifically, in contrast to c-REL inactivation, deletion of rela in germinal center B cells did not affect germinal center maintenance, but impaired the generation of germinal center-derived plasma cells [59▪]. The precise mechanism by which RELA induces terminal differentiation in concert with other transcriptional regulators required for plasma cell development remains to be determined. However, in vitro experiments suggest that RELA contributes to the transcription factor network that controls plasma cell differentiation by upregulating the expression of the plasma cell regulator BLIMP1 [59▪].

IMPLICATIONS FOR GERMINAL CENTER LYMPHOMAGENESIS

REL has been identified as a viral oncogene causing reticuloendotheliosis in birds [70]. The amplification of the REL locus in several types of B-cell lymphomas [17,42–44] and the occurrence in lymphomas of genetic mutations leading to constitutive activation of the canonical NF-κB pathway suggest an oncogenic function for c-REL also in humans. The finding that in normal germinal center B cells, c-REL-deficiency results in the failure to establish a metabolic program required for cell growth [59▪] may in turn suggest that aberrantly elevated c-REL activity could be oncogenic by enhancing cellular metabolism with direct effects on cell growth (Fig. 3). Gene expression profiling has allowed the classification of DLBCL cases into subtypes that show differences in the particular metabolic program of the tumor cells [18]. One subgroup is characterized by the expression of genes involved in oxidative phosphorylation (OxPhos), and it has been noted that DLBCL cases corresponding to a non-OxPhos subgroup (mostly comprising cases with a signature relating to B-cell receptor signaling/proliferation) show enhanced glycolytic flux [71]. It will be interesting to determine the extent to which c-REL activation contributes to the respective metabolic phenotypes.

FIGURE 3
FIGURE 3:
Hypothesis: consequences of c-REL or RELA deregulation in germinal center B cells or plasma cells. As a result of its role in germinal center B-cell metabolism and growth, aberrant c-REL activity might promote tumorigenesis by allowing the cell to bypass affinity selection in the germinal center and recirculate between dark zone (DZ) and light zone (LZ) in an uncontrolled fashion. In contrast, aberrant RELA activity in germinal center B cells may disturb the physiological processes controlling the development of plasma cells. B, B cell; T, T cell; FDC, follicular dendritic cell.

c-REL appears to maintain the germinal center reaction by licensing the recirculation of antigen-selected B cells from the light zone back to the dark zone. Such a light zone–dark zone reentry function has previously been established for the c-MYC proto-oncogene [66,67], whose expression is deregulated in several germinal center lymphoma subtypes. It has been suggested that in germinal center lymphomas with MYC translocations, constitutive expression of c-MYC may promote tumorigenesis by forcing the B cell to bypass the normal affinity selection step in the light zone and to continuously recirculate between light zone and dark zone [66]. Deregulated c-REL activity may similarly perturb the normal dynamics of the germinal center reaction (Fig. 3). It is tempting to speculate that the aberrant activities of these transcription factors exert oncogenic roles specifically in the subpopulation of light zone B cells that undergo antigen selection by preventing their further differentiation into memory or plasma cells. During germinal center development, this likely occurs at a cellular stage that precedes the plasmablastic stage in which PRDM1 inactivation or constitutive BCL6 activity is thought to inhibit terminal differentiation [9].

Among DLBCL cases, MYC translocations and REL amplifications occur predominantly in the germinal center subtype. It has been noted that in germinal center-DLBCL with amplification of REL, there is a lack of correlation between REL amplification and nuclear translocation of the subunit [72]. Clearly, increased levels of c-REL are unlikely to be biologically active unless the canonical pathway is induced. In germinal center-DLBCL, that, in contrast to ABC-DLBCL, is rarely associated with activating mutations in the canonical NF-κB pathway, one could envision that stimuli by the tumor microenvironment in a small fraction of cells may drive c-REL into the nucleus. Enhanced protein levels of c-REL would then lead to an altered NF-κB response in thus stimulated germinal center-DLBCL tumor cells. With regard to other germinal center-derived tumor types, c-REL is found in the nucleus of a large fraction of tumor cells in many DLBCLs, mostly of the ABC type [72] and in Hodgkin lymphoma and MLBCL regardless of amplification of the REL locus [15–17]. Mutations in upstream components of the canonical NF-κB pathway, such as A20, may lead to the continuous translocation of c-REL/p50 heterodimers into the nucleus. It will be interesting to determine the specific biological programs controlled by c-REL in the corresponding tumor cells.

Aberrant RELA activity in germinal center B cells may impose a biological program onto the cell that is associated with plasma cell differentiation or physiology (Fig. 3). Besides ABC-DLBCL, constitutive RELA activation has been associated with multiple myeloma [27,28], where it may render the tumor cells less dependent on NF-κB activation mediated by ligands that are required for the survival of plasma cells within the bone-marrow niches, allowing stromal-independent tumor cell growth. Future work is needed to define the precise function of RELA in germinal center lymphomas and multiple myeloma.

A role for the alternative NF-κB pathway during the germinal center reaction is highly likely in light of the fact that CD40 stimulation (which occurs in a subset of light zone B cells) strongly activates this pathway, and because several genetic aberrations lead to the predominant activation of this signaling route. Indeed, the contribution of this pathway to lymphomagenesis is actively being explored [73,74]. Importantly, a recent study provides functional evidence for a role of aberrant activation of the alternative NF-κB pathway in germinal center lymphomagenesis. Mice with constitutive activation of NF-κB-inducing kinase (NIK), a critical upstream component of the alternative pathway, specifically in germinal center B cells led to DLBCL development upon simultaneous deregulation of BCL6 expression [36]. The study further provides evidence that constitutive NIK activity in germinal center B cells promotes plasma cell hyperplasia; upon blocking terminal differentiation by deregulated BCL6 expression, lymphomas developed. It will be interesting to identify the precise roles of the alternative NF-κB subunits RELB and p100/p52 in germinal center development.

Finally, the ability to identify the targets to which the individual NF-κB subunits bind will help to better understand the selectivity of the NF-κB response [75]. In addition, the precise dissection of the signaling network upstream of the transcription factor subunits will help to better define NF-κB pathway activation [76▪,77]. The ultimate goal should be to inhibit only those components of aberrant NF-κB activity that are pathogenic, ideally at the level of NF-κB subunits to ensure the highest specificity [78]. In this regard, the recent characterization of a small molecule c-REL inhibitor may hold promise for the development of anticancer therapies that enable targeting of individual NF-κB subunits [79▪].

CONCLUSION

It is now firmly established that aberrant activity of the NF-κB pathway plays an important role in B-cell lymphomagenesis. It is also becoming clear that distinct B-cell tumors are characterized by a preferential activity of the canonical or alternative NF-κB pathways and presumably also individual NF-κB subunits. This specificity may be exploited for the development of targeted therapies aimed at inhibiting selectively those components of the NF-κB pathway that directly contribute to pathogenesis. Unraveling the selectivity of the NF-κB response in normal and cancerous B cells will be instrumental in this undertaking.

Acknowledgements

We thank Laura Pasqualucci for comments on the manuscript and the members of the Klein lab for discussions.

Financial support and sponsorship

This work was supported by NCI/NIH grant R01-CA157660 to U.K. and by a fellowship from the German Research Council (DFG) to N.H.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

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Keywords:

B-cell lymphoma; germinal center; lymphomagenesis; nuclear factor-κB

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