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].
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 . 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.
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  or as a result of infection with tumor viruses such as Epstein–Barr virus or Karposi's sarcoma-associated herpesvirus . 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 .
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 , 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 . 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  and stimulation of CLL cells mediated by the tumor environment . Recurrent mutations were identified in a negative regulator of the alternative NF-κB pathway in about ∼10% of CLL cases  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  (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 , 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 , 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 , 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 . 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 . 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 . 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 . It will be interesting to determine the extent to which c-REL activation contributes to the respective metabolic phenotypes.
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 . 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 .
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 . 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  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 . 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 . 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 . 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▪].
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.
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
1. Stevenson F, Sahota S, Zhu D, et al. Insight into the origin and clonal history of B-cell tumors as revealed by analysis of immunoglobulin variable region genes. Immunol Rev 1998; 162:247–259.
2. Küppers R, Klein U, Hansmann ML, et al. Cellular origin of human B-cell lymphomas. N Engl J Med 1999; 341:1520–1529.
3. MacLennan IC. Germinal centers. Annu Rev Immunol 1994; 12:117–139.
4. Rajewsky K. Clonal selection and learning in the antibody system. Nature 1996; 381:751–758.
5. Allen CD, Okada T, Cyster JG. Germinal-center organization and cellular dynamics. Immunity 2007; 27:190–202.
6. Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol 2012; 30:429–457.
7. Küppers R. Mechanisms of B-cell lymphoma
pathogenesis. Nat Rev Cancer 2005; 5:251–262.
8. Klein U, Dalla-Favera R. Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 2008; 8:22–33.
9. Shaffer AL 3rd, Young RM, Staudt LM. Pathogenesis of human B cell lymphomas. Annu Rev Immunol 2012; 30:565–610.
10. Hayden MS, Ghosh S. Signaling to NF-κB. Genes Dev 2004; 18:2195–2224.
11. Vallabhapurapu S, Karin M. Regulation and function of NF-κB transcription factors in the immune system. Annu Rev Immunol 2009; 27:693–733.
12. Gerondakis S, Siebenlist U. Roles of the NF-κB pathway in lymphocyte development and function. Cold Spring Harb Perspect Biol 2010; 2:a000182.
13. Kaileh M, Sen R. NF-κB function in B lymphocytes. Immunol Rev 2012; 246:254–271.
14. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma
identified by gene expression profiling. Nature 2000; 403:503–511.
15. Rosenwald A, Wright G, Leroy K, 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 2003; 198:851–862.
16. Savage KJ, Monti S, Kutok JL, et al. The molecular signature of mediastinal large B-cell lymphoma
differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 2003; 102:3871–3879.
17. Feuerhake F, Kutok JL, Monti S, et al. NF-κB activity, function, and target-gene signatures in primary mediastinal large B-cell lymphoma
and diffuse large B-cell lymphoma
subtypes. Blood 2005; 106:1392–1399.
18. Monti S, Savage KJ, Kutok JL, et al. Molecular profiling of diffuse large B-cell lymphoma
identifies robust subtypes including one characterized by host inflammatory response. Blood 2005; 105:1851–1861.
19. Hideshima T, Chauhan D, Richardson P, et al. NF-κB as a therapeutic target in multiple myeloma. J Biol Chem 2002; 277:16639–16647.
20. Herishanu Y, Perez-Galan P, Liu D, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 2011; 117:563–574.
21. Sun SC, Cesarman E. NF-κB as a target for oncogenic viruses. Curr Top Microbiol Immunol 2011; 349:197–244.
22. Lenz G, Davis RE, Ngo VN, et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 2008; 319:1676–1679.
23. Compagno M, Lim WK, Grunn A, et al. Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma
. Nature 2009; 459:717–721.
24. Kato M, Sanada M, Kato I, et al. Frequent inactivation of A20 in B-cell lymphomas. Nature 2009; 459:712–716.
25. Schmitz R, Hansmann ML, Bohle V, et al. TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med 2009; 206:981–989.
26. Novak U, Rinaldi A, Kwee I, et al. The NF-κB negative regulator TNFAIP3 (A20) is inactivated by somatic mutations and genomic deletions in marginal zone lymphomas. Blood 2009; 113:4918–4921.
27. Annunziata CM, Davis RE, Demchenko Y, et al. Frequent engagement of the classical and alternative NF-κB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 2007; 12:115–130.
28. Keats JJ, Fonseca R, Chesi M, et al. Promiscuous mutations activate the noncanonical NF-κB pathway in multiple myeloma. Cancer Cell 2007; 12:131–144.
29. Demchenko YN, Glebov OK, Zingone A, et al. Classical and/or alternative NF-κB pathway activation in multiple myeloma. Blood 2010; 115:3541–3552.
30. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma
. Nature 2010; 463:88–92.
31. Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 2011; 470:115–119.
32. Jungnickel B, Staratschek-Jox A, Brauninger A, et al. Clonal deleterious mutations in the IκBα gene in the malignant cells in Hodgkin's lymphoma. J Exp Med 2000; 191:395–402.
33. Calado DP, Zhang B, Srinivasan L, 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 2010; 18:580–589.
34. Pasqualucci L, Trifonov V, Fabbri G, et al. Analysis of the coding genome of diffuse large B-cell lymphoma
. Nat Genet 2011; 43:830–837.
35. Bushell KR, Kim Y, Chan FC, et al. Genetic inactivation of TRAF3 in canine and human B-cell lymphoma
. Blood 2015; 125:999–1005.
36. Zhang B, Calado DP, Wang Z, et al. An oncogenic role for alternative NF-κB signaling in DLBCL revealed deregulated BCL6 expression. Cell Rep 2015; 11:715–726.
37. Steidl C, Telenius A, Shah SP, et al. Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome. Blood 2010; 116:418–427.
38. Otto C, Giefing M, Massow A, et al. Genetic lesions of the TRAF3 and MAP3K14 genes in classical Hodgkin lymphoma. Br J Hematol 2012; 157:702–708.
39. Rossi D, Deaglio S, Dominguez-Sola D, et al. Alteration of BIRC3 and multiple other NF-κB pathway genes in splenic marginal zone lymphoma. Blood 2011; 118:4930–4934.
40▪. Rahal R, Frick M, Romero R, et al. Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma. Nat Med 2014; 20:87–92.
This study identifies NIK as a new therapeutic target for mantle cell lymphoma treatment for the subset of lymphomas that are refractory to BCR pathway inhibitors.
41. Hideshima T, Chauhan D, Kiziltepe T, et al. Biologic sequelae of IκB kinase (IKK) inhibition in multiple myeloma: therapeutic implications. Blood 2009; 113:5228–5236.
42. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma
. N Engl J Med 2002; 346:1937–1947.
43. Martin-Subero JI, Gesk S, Harder L, et al. Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma. Blood 2002; 99:1474–1477.
44. Barth TF, Martin-Subero JI, Joos S, et al. Gains of 2p involving the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells of classical Hodgkin lymphoma. Blood 2003; 101:3681–3686.
45. Hewamana S, Alghazal S, Lin TT, et al. The NF-κB subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target. Blood 2008; 111:4681–4689.
46. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med 2005; 352:804–815.
47. Rossi D, Fangazio M, Rasi S, et al. Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia. Blood 2012; 119:2854–2862.
48. Puente XS, Pinyol M, Quesada V, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 2011; 475:101–105.
49. Wang L, Lawrence MS, Wan Y, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 2011; 365:2497–2506.
50▪. Damm F, Mylonas E, Cosson A, et al. Acquired initiating mutations in early hematopoietic cells of CLL patients. Cancer Discov 2014; 4:1088–1101.
This study identifies recurrent mutations of the NF-κB pathway component NFKBIE in CLL.
51. Shaffer AL, Rosenwald A, Hurt EM, et al. Signatures of the immune response. Immunity 2001; 15:375–385.
52. Basso K, Klein U, Niu H, et al. Tracking CD40 signaling during germinal center
development. Blood 2004; 104:4088–4096.
53. Li Z, Wang X, Yu RY, et al. BCL-6 negatively regulates expression of the NF-κB1 p105/p50 subunit. J Immunol 2005; 174:205–214.
54. Köntgen F, Grumont RJ, Strasser A, et al. Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Genes Dev 1995; 9:1965–1977.
55. Tumang JR, Owyang A, Andjelic S, et al. c-Rel is essential for B lymphocyte survival and cell cycle progression. Eur J Immunol 1998; 28:4299–4312.
56. Carrasco D, Cheng J, Lewin A, et al. Multiple hemopoietic defects and lymphoid hyperplasia in mice lacking the transcriptional activation domain of the c-Rel protein. J Exp Med 1998; 187:973–984.
57. Damdinsuren B, Zhang Y, Khalil A, et al. Single round of antigen receptor signaling programs naive B cells to receive T cell help. Immunity 2010; 32:355–366.
58. Pohl T, Gugasyan R, Grumont RJ, et al. The combined absence of NF-κB1 and c-Rel reveals that overlapping roles for these transcription factors in the B cell lineage are restricted to the activation and function of mature cells. Proc Natl Acad Sci USA 2002; 99:4514–4519.
59▪. Heise N, De Silva NS, Silva K, et al. Germinal center
B cell maintenance and differentiation are controlled by distinct NF-κB transcription factor subunits. J Exp Med 2014; 211:2103–2118.
This study demonstrates that the canonical NF-κB subunit c-REL is required for the maintenance of the germinal center B-cell reaction, presumably by activating a metabolic program that promotes cell growth which may have implications for the potential role of c-REL in lymphomagenesis.
60. Wang R, Dillon CP, Shi LZ, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 2011; 35:871–882.
61. van der Windt GJ, Pearce EL. Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol Rev 2012; 249:27–42.
62. Man K, Miasari M, Shi W, et al. The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells. Nat Immunol 2013; 14:1155–1165.
63. Sinclair LV, Rolf J, Emslie E, et al. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol 2013; 14:500–508.
64. Grumont RJ, Strasser A, Gerondakis S. B cell growth is controlled by phosphatidylinosotol 3-kinase-dependent induction of Rel/NF-κB regulated c-myc transcription. Mol Cell 2002; 10:1283–1294.
65. Mauro C, Leow SC, Anso E, et al. NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration. Nat Cell Biol 2011; 13:1272–1279.
66. Dominguez-Sola D, Victora GD, Ying CY, et al. The proto-oncogene MYC is required for selection in the germinal center
and cyclic reentry. Nat Immunol 2012; 13:1083–1091.
67. Calado DP, Sasaki Y, Godinho SA, et al. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nat Immunol 2012; 13:1092–1100.
68. Beg AA, Sha WC, Bronson RT, et al. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB. Nature 1995; 376:167–170.
69. Doi TS, Takahashi T, Taguchi O, et al. NF-κB RelA-deficient lymphocytes: normal development of T cells and B cells, impaired production of IgA and IgG1 and reduced proliferative responses. J Exp Med 1997; 185:953–961.
70. Gilmore TD. Multiple mutations contribute to the oncogenicity of the retroviral oncoprotein v-Rel. Oncogene 1999; 18:6925–6937.
71. Caro P, Kishan AU, Norberg E, et al. Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell 2012; 22:547–560.
72. Houldsworth J, Olshen AB, Cattoretti G, et al. Relationship between REL amplification, REL function, and clinical and biologic features in diffuse large B-cell lymphomas. Blood 2004; 103:1862–1868.
73. Ramachandiran S, Adon A, Guo X, et al. Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF-κB pathway. Int J Cancer 2015; 136:2341–2351.
74. Ranuncolo SM, Pittaluga S, Evbuomwan MO, et al. Hodgkin lymphoma requires stabilized NIK and constitutive RelB expression for survival. Blood 2012; 120:3756–3763.
75. Zhao B, Barrera LA, Ersing I, et al. The NF-κB genomic landscape in lymphoblastoid B cells. Cell Rep 2014; 8:1595–1606.
76▪. Nogai H, Wenzel SS, Hailfinger S, et al. IκB-ζ controls the constitutive NF-κB target gene network and survival of ABC DLBCL. Blood 2013; 122:2242–2250.
This study shows that IκB-ζ is essential for nuclear NF-κB activity in the ABC-type DLBCL, identifying IκB-ζ as a potential therapeutic target.
77. Rosebeck S, Rehman AO, Apel IJ, et al. The API2-MALT1 fusion exploits TNFR pathway-associated RIP1 ubiquitination to promote oncogenic NF-κB signaling. Oncogene 2014; 33:2520–2530.
78. Perkins ND. The diverse and complex roles of NF-κB subunits in cancer. Nat Rev Cancer 2012; 12:121–132.
79▪. Shono Y, Tuckett AZ, Ouk S, et al. A small-molecule c-Rel inhibitor reduces alloactivation of T cells without compromising antitumor activity. Cancer Discovery 2014; 4:578–591.