Submitted by Ívy Rafacho Vieira null (ivy.raff@yahoo.com.br) on 2017-02-20T18:11:01Z No. of bitstreams: 1 Dissertação final mesmo Ivy.pdf: 2121270 bytes, checksum: ae8b49d15e98a6f5efb7ad097fe78b38 (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-02-22T20:26:44Z (GMT) No. of bitstreams: 1 vieira_ir_me_bot.pdf: 2121270 bytes, checksum: ae8b49d15e98a6f5efb7ad097fe78b38 (MD5) / Made available in DSpace on 2017-02-22T20:26:44Z (GMT). No. of bitstreams: 1 vieira_ir_me_bot.pdf: 2121270 bytes, checksum: ae8b49d15e98a6f5efb7ad097fe78b38 (MD5) Previous issue date: 2017-01-20 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A paracoccidioidomicose (PCM) é uma micose sistêmica, endêmica na América Latina, causada pela inalação de propágulos micelianos do fungo termodimórfico do gênero Paracoccidioides spp.(Pb). Dentre os mecanismos de resposta imune contra o fungo, destacam-se os exercidos pelas células fagocitárias como os macrófagos, neutrófilos e células dendríticas (DCs). Além do importante papel efetor, isto é, de destruição do fungo, essas células, por terem capacidade de produzir citocinas tanto pró como anti-inflamatórias, desempenham um importante papel modulador da resposta imune inata, assim como de instrução da resposta imune adaptativa que será gerada posteriormente. Para essa última função, as células dendríticas merecem destaque por constituírem a população de células fagocitárias mais adaptada ao processo de ligar, fagocitar, destruir, processar microrganismos e após migrarem aos órgãos linfóides periféricos, locais onde elas maturam para desenvolver o processo de apresentação de antígeno, desencadear e instruir a resposta imune adaptativa. No entanto, de forma similar às outras células fagocíticas, as DCs são capazes de liberar potentes moléculas citotóxicas que as capacita a destruírem eficientemente os microrganismos. Essa capacidade, embora necessária ao papel modulador das DCs citado acima, representa um mecanismo efetor importante durante a resposta imune inata. A maior ou menor capacidade das DCs destruírem os vários microrganismos pode resultar em diferenças na disseminação dos mesmos durante a migração dessas células da periferia até os órgãos linfóides secundários. Neste contexto, em estudo anterior avaliamos se DCs humanas exercem atividade fungicida contra o P. brasiliensis e se esse processo envolve a ativação do sistema NADPHoxidase com consequente produção de H2O2, o metabolito envolvido na destruição do P. brasiliensis. Detectamos que as DCs não liberam níveis adequados de H2O2 e consequentemente não desenvolvem atividade fungicida contra o P. brasiliensis. Em outro estudo observamos que a interação das DCs com o Pb não resulta em maturação eficiente dessas células. O tipo de receptor de reconhecimento padrão (PRR) ao qual o fungo se liga pode determinar o seu destino no interior das células fagocitárias. Estudos têm mostrado que enquanto alguns deles estão envolvidos na replicação dos microrganismos no interior das células fagocíticas, ao contrário, outros participam da destruição dos mesmos. Nesse sentido, estudos sugerem que a estimulação de TLR9 através do ligante agonista CpG-ODN culmina com ativação do metabolismo oxidativo e consequente destruição de patógenos. Corroborando com esses estudos, detectamos que a incubação de DCs humanas com um agonista do TLR9 induziu um aumento significativo na atividade fungicida dessa células contra o P.brasiliensis . No entanto, esse efeito não esteve associado à um aumento da produção de H2O2. / Paracoccidioidomycosis (PCM) is a systemic mycosis, endemic to Latin America, caused by the inhalation of mycelial propagules of the thermodymorphic fungus of the genus Paracoccidioides spp. (Pb). Among the mechanisms of immune response against the fungus, we highlight those exerted by phagocytic cells such as macrophages, neutrophils and dendritic cells (DCs). In addition to their important effector role, that is, fungus destruction, these cells, due to the capacity to produce both pro and anti-inflammatory cytokines, play an important role in modulating the innate immune response, as well as instructing the adaptive immune response. For this latter function, DCs deserve special attention, as they are the phagocytic cells population more adapted to the process of binding, phagocytizing, destroying, processing microorganisms and after migrate to the peripheral lymphoid organs, where they mature and instruct the adaptive immune response. However, similarly to other phagocytic cells, DCs are able to release potent cytotoxic molecules that enable them to efficiently destroy microorganisms. This ability, although necessary to their modulatory role cited above, represents an important effector mechanism during the innate immune response. The higher or lower capacity of DCs to destroy the various microorganisms may result in differences in dissemination of the infection during the migration of these cells from the periphery to the secondary lymphoid organs. In this context, in a previous study we evaluated whether human DCs exert fungicidal activity against P. brasiliensis and whether this process involves the activation of the NADP oxidase system with consequent H2O2 production, the metabolite involved in the P. brasiliensis killing. We have detected that DCs do not release adequate levels of H2O2 and consequently do not exert fungicidal activity against P. brasiliensis. In another study, we observed that the interaction of DCs with Pb does not result in efficient maturation of these cells. The type of pattern recognition receptor (PRR) to which the fungus binds can determine its fate within the phagocytic cells. Studies have shown that while some PRRs are associated to the replication of microorganisms within the phagocytic cells, other, on the contrary, are involved in the mechanisms of pathogens killing. In this sense, studies suggested that TLR9 stimulation by the agonist CpG-ODN culminates with oxidative metabolism activation and pathogens elimination. Accordinly, in our study we detected that human DCs incubation with a TLR9 agonist results in a significant increase of the fungicidal activity of these cells against P.brasiliensis. However, this effect was not associated with an increase in H2O2 production.

As phosphorylation represents the pivotal mechanism for regulation of biological processes, kinases belong to one of the most biologically significant enzyme classes. The development of analytical techniques for characterization of kinase activity, in particular at a global scale, is a central priority for proteomic and cell biology researchers. In order to facilitate global analysis of cellular phosphorylation, a new paradigm of microarray technology which focuses on analysis of total cellular kinase activity, kinome, has emerged in the past few years. As the specificity of many kinases is dictated primarily by recognition of residues immediately surrounding the site of phosphorylation a logical methodology is to employ peptides representing these immediate sequences as experimental substrates. Microarray chips carrying hundreds of such substrate targets have been developed for human kinome analysis, however, lack of similar tools for species outside research mainstream has limited kinome analysis in these species.<p> Based on sequence alignment of orthologous phosphoproteins from mammalian species, conservation of amino acid identity is reported to be 80 %. Accordingly, the potential exists to utilize phosphorylation sequence databases to extrapolate phosphorylation sites in other species based on their genomic sequence information. Peptides representing these proposed phosphorylation sites can then be utilized as substrates to quantify the activity of the corresponding kinase. Based on these principles, a bovine microarray of 300 unique peptide targets was constructed. The bovine phosphorylation targets were selected to represent a spectrum of cellular events but with focus on processes related to innate immunity. Initial application and validation of the bovine peptide arrays was carried out for kinome analysis of bovine blood monocytes stimulated with either lipopolysaccharide (LPS) or CpG-ODNs; ligands for Toll-like receptors (TLR) 4 and 9, respectively. The arrays confirmed activation of the known TLR signaling pathway as well as identifying receptor-specific phosphorylation events. Phosphorylation events not previously attributed to TLR activation were also identified and validated by independent bioassays. This investigation offers insight into the complexity of TLR signaling and more importantly verifies the potential to use bioinformatics approaches to create tools for species-specific kinome analysis based on genomic information.

As phosphorylation represents the pivotal mechanism for regulation of biological processes, kinases belong to one of the most biologically significant enzyme classes. The development of analytical techniques for characterization of kinase activity, in particular at a global scale, is a central priority for proteomic and cell biology researchers. In order to facilitate global analysis of cellular phosphorylation, a new paradigm of microarray technology which focuses on analysis of total cellular kinase activity, kinome, has emerged in the past few years. As the specificity of many kinases is dictated primarily by recognition of residues immediately surrounding the site of phosphorylation a logical methodology is to employ peptides representing these immediate sequences as experimental substrates. Microarray chips carrying hundreds of such substrate targets have been developed for human kinome analysis, however, lack of similar tools for species outside research mainstream has limited kinome analysis in these species.<p> Based on sequence alignment of orthologous phosphoproteins from mammalian species, conservation of amino acid identity is reported to be 80 %. Accordingly, the potential exists to utilize phosphorylation sequence databases to extrapolate phosphorylation sites in other species based on their genomic sequence information. Peptides representing these proposed phosphorylation sites can then be utilized as substrates to quantify the activity of the corresponding kinase. Based on these principles, a bovine microarray of 300 unique peptide targets was constructed. The bovine phosphorylation targets were selected to represent a spectrum of cellular events but with focus on processes related to innate immunity. Initial application and validation of the bovine peptide arrays was carried out for kinome analysis of bovine blood monocytes stimulated with either lipopolysaccharide (LPS) or CpG-ODNs; ligands for Toll-like receptors (TLR) 4 and 9, respectively. The arrays confirmed activation of the known TLR signaling pathway as well as identifying receptor-specific phosphorylation events. Phosphorylation events not previously attributed to TLR activation were also identified and validated by independent bioassays. This investigation offers insight into the complexity of TLR signaling and more importantly verifies the potential to use bioinformatics approaches to create tools for species-specific kinome analysis based on genomic information.

Orientador: Ângela Maria Victoriano de Campos Soares / Resumo: A paracoccidioidomicose (PCM) é uma micose sistêmica, endêmica na América Latina, causada pela inalação de propágulos micelianos do fungo termodimórfico do gênero Paracoccidioides spp.(Pb). Dentre os mecanismos de resposta imune contra o fungo, destacam-se os exercidos pelas células fagocitárias como os macrófagos, neutrófilos e células dendríticas (DCs). Além do importante papel efetor, isto é, de destruição do fungo, essas células, por terem capacidade de produzir citocinas tanto pró como anti-inflamatórias, desempenham um importante papel modulador da resposta imune inata, assim como de instrução da resposta imune adaptativa que será gerada posteriormente. Para essa última função, as células dendríticas merecem destaque por constituírem a população de células fagocitárias mais adaptada ao processo de ligar, fagocitar, destruir, processar microrganismos e após migrarem aos órgãos linfóides periféricos, locais onde elas maturam para desenvolver o processo de apresentação de antígeno, desencadear e instruir a resposta imune adaptativa. No entanto, de forma similar às outras células fagocíticas, as DCs são capazes de liberar potentes moléculas citotóxicas que as capacita a destruírem eficientemente os microrganismos. Essa capacidade, embora necessária ao papel modulador das DCs citado acima, representa um mecanismo efetor importante durante a resposta imune inata. A maior ou menor capacidade das DCs destruírem os vários microrganismos pode resultar em diferenças na disseminaçã... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Sepsis, a major clinical problem with high morbidity and mortality, is caused by overwhelming systemic host-inflammatory response. Toll-like receptors (TLRs) play a fundamental role in induction of hyperinflammation and tissue damage in sepsis. In this study, we demonstrate a protective role of TLR9 inhibition against the dysregulated inflammatory response and tissue injury in sepsis. TLR9 deficiency decreased the mortality of mice following cecal ligation and puncture (CLP)-induced sepsis. TLR9 knockout mice showed dampened p38 activation and augmented Akt phosphorylation in the spleen, lung and liver. In addition, TLR9 deficiency decreased the levels of inflammatory cytokines and attenuated splenic apoptosis after CLP. These results indicate that TLR9 inhibition might offer a novel therapeutic strategy for the management of sepsis.

Activation of TLRs mediated the NF-κB signaling pathway plays an important pathophysiological role in cardiac hypertrophy. Triad3A, a ubiquitin E3 ligase, has been reported to negatively regulate NF-κB activation pathway via promoting ubiquitination and degradation of TLR4 and TLR9 in innate immune cells. The role of Triad3A in cardiac hypertrophic development remains unknown. The present study investigated whether there is a link between Triad3A and TLR4 and TLR9 in pressure overload induced cardiac hypertrophy. We observed that Triad3A levels were markedly reduced following transverse aortic constriction (TAC) induced cardiac hypertrophy. Similarly, stimulation of neonatal rat cardiac myocytes (NRCMs) with angiotensin-II (Ang II) significantly decreased Triad3A expression. To determine the role of Triad3A in TAC-induced cardiac hypertrophy, we transduced the myocardium with adenovirus expressing Triad3A followed by induction of TAC. We observed that increased expression of Triad3A significantly attenuated cardiac hypertrophy and improved cardiac function. To investigate the mechanisms by which Triad3A attenuated cardiac hypertrophy, we examined the Triad3A E3 ubiquitination on TLR4 and TLR9. We found that Triad3A promoted TLR4 and TLR9 degradation through ubiquitination. Triad3A mediated TLR4 and TLR9 degradation resulted in suppression of NF-κB activation. Our data suggest that Triad3A plays a protective role in the development of cardiac hypertrophy, at least through catalyzing ubiquitination-mediated degradation of TLR4 and TLR9, thus negatively regulating NF-κB activation.

Le syndrome de Gougerot-Sjögren (SGS) est une maladie auto-immune systémique. Il se caractérise principalement par une infiltration lymphocytaire des glandes salivaires (GS) et lacrymales responsable d’une sécheresse buccale et oculaire. Par ailleurs,les Toll-like récepteurs (TLR) endosomaux – notamment le TLR9 qui reconnait l’acide désoxyribonucléique (ADN) microbien mais aussi, dans certaines conditions, l’ADN du soi –s’avèrent être importants pour l’activation des lymphocytes B (LB) lors du lupus, une maladie proche du SGS. Nos travaux montrent que la stimulation du TLR9 chez les LB transitionnels,des LB immatures fraichement émigrés de la moelle osseuse, favorise leur différenciation selon la voie des LB de la zone marginale, et entraine la sécrétion d’auto-anticorps. L’analyse des LB infiltrant les GS lors du SGS révèle que ce phénomène pourrait être impliqué dans la physiopathologie de cette maladie. De plus, nous montrons que LL37, un peptide produit dans les GS, pourrait participer à l’activation du TLR9 des LB transitionnels. Enfin, nous avons mis en évidence une inattendue expression du TLR9 à la surface des LB. Si l’étude des conséquences fonctionnelles de cette localisation reste à poursuivre, elle semble avoir un effet négatif sur la stimulation du TLR9 endosomal. En conclusion, ces résultats suggèrent que leTLR9 puisse être une nouvelle cible thérapeutique lors du SGS. / Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease. It is mainly characterized by B cell and T cell infiltration in lacrimal and salivary glands (SG) responsible for eye and mouth dryness. In addition, endosomal Toll-like receptors (TLR) – especially TLR9 which recognizes microbial deoxyribonucleic acid (DNA) and also, under certain conditions, self DNA – are important for B cell activation during lupus, a disease close topSS. Our work shows that TLR9 stimulation on transitional B cells, immature B cells freshly emigrated from bone marrow, promotes their differentiation into marginal zone B cell pathway and drives to auto-antibodies production. Analysis of infiltrating B cells in pSS SG reveals that this phenomenon might be involved in the pathogenesis of the disease.Furthermore, we show that LL37, a peptide produced in the SG, could participate in TLR9activation of transitional B cells. Finally, we demonstrated an unexpected TLR9 expression on B cell surface. If the functional consequences of this localization remain to be more precisely evaluated, it seems that cell surface TLR9 has a negative effect on endosomal TLR9 stimulation. In conclusion, these results suggest TLR9 could be a new therapeutic target incase of pSS.

L’infection chronique est à l’origine de 15-20% des cancers dans le monde. Dans la plupart des cas, les infections sont éliminées par le système immunitaire, sans incidence importante sur les hôtes infectés. Toutefois, les oncovirus peuvent échapper au système immunitaire et induire une transformation cellulaire, ce qui constitue deux éléments clés de la cancérogenèse associée aux virus. L’EBV est un herpesvirus ubiquitaire à ADN double brin qui infecte plus de 90% de la population, avec un tropisme spécifique pour les cellules B. Après primo-infection, le virus persiste dans l’hôte pour toujours. L’EBV est responsable de la mononucléose infectieuse bénigne et est associé à plusieurs tumeurs malignes telles que le lymphome de Burkitt, le lymphome de Hodgkin et certaines formes de cancers gastriques. Les récepteurs Toll-like (TLRs) mammaires jouent un rôle important dans la défense de l’hôte lors de l’infection pathogène en régulant et reliant les réponses immunitaires innées et adaptatives. Dans cette étude, nous avons montré que l’EBV pouvait altérer la régulation et l’expression de TLR9, une des molécules effectrices majeures de la réponse immunitaire innée. L’infection par l’EBV des lymphocytes B primaires humains a entraîné l’inhibition de la fonctionnalité de TLR9. Nous avons observé que l’EBV exerçait sa fonction inhibitrice en diminuant les niveaux d’ARNm et de la protéine du récepteur TLR9. De plus, nous avons établi que LMP1, oncoprotéine majeure de l’EBV, inhibait fortement la transcription de TLR9. La sur-expression de LMP1 par transfection transitoire ou transduction des cellules B réduit l’activité du promoteur de TLR9, l’ARNm et les niveaux protéiques. Bloquer la voie de signalisation de NF-κB induite par la signalisation de LMP1 permet de récupérer l’activité du promoteur de TLR9 et l’expression de la protéine. L’ensemble de nos résultats mettent en évidence un nouveau mécanisme utilisé par l’EBV pour supprimer la réponse immunitaire de l’hôte en dérégulant la transcription de TLR9 via l’activation de NF-κB par LMP1 / Chronic infection causes about 15-20% of cancer worldwide. In most cases, infections are cleared by the immune system with no dramatic consequence for the infected hosts. However, oncoviruses can escape the immune system and induce cellular transformation, two key events in cancer mediated by viruses. EBV is a ubiquitous double-stranded DNA herpesvirus, which infects more than 90% of the population with a specific tropism to B-cells. Upon primo-infection the virus persists in the host for lifetime. EBV is responsible of the benign infectious mononucleosis and is associated to several malignancies such as the Burkitt lymphoma, Hodgkin’s lymphoma and some forms of gastric cancers. Mammalian Toll-like receptors (TLRs) play a key role in host defense during pathogen infection by regulating and linking the innate and adaptive immune responses. TLRs belong to a family of receptors that recognize pathogen-associated molecular patterns and are expressed on immune and non-immune cells, endowing them with the capacity to sense pathogen-derived products and to alert the immune system . In this study we show that EBV can alter the regulation and expression of TLR9, one of the key effector molecules of the innate immune response. EBV infection of human primary B cells resulted in the inhibition of TLR9 functionality. Stimulation of TLR9 on primary B cells led to the production of IL-6, TNFα and IgG, which was inhibited in cells infected with EBV. We observed that EBV exerts its inhibitory function by decreasing TLR9 mRNA and protein levels. This event was observed twelve hours post EBV infection of primary cells as well as in an immortalized B cell line, demonstrating the specific role of the virus to turn down TLR9 levels. In addition, we determined that the EBV oncoprotein LMP1 is a strong inhibitor of TLR9 transcription. Over expression of LMP1 by transient transfection or transduction of B cells, reduced TLR9 promoter activity, mRNA and protein levels. Blocking the NF-κB pathway induced by LMP1 signaling, recovered TLR9 promoter activity and protein expression. Moreover LMP1 mutants deficient in activating the NF-κB pathway inversely restored TLR9 transcription. Taken together, our study reveals a novel mechanism used by EBV to suppress the host immune response by deregulating the TLR9 transcript through LMP1-mediated NF-κB activation

A L. (L.) amazonensis é capaz de evadir a resposta imune do macrófago hospedeiro induzindo a expressão de CD200 na célula. Porém, ainda não se sabe como ocorre este mecanismo. O objetivo deste trabalho foi avaliar a participação dos TLRs na indução de CD200 em macrófagos infectados por L. (L.) amazonensis. Os resultados mostraram que a indução de CD200 por L. (L.) amazonensis é dependente de TLR9 e das proteínas adaptadoras MyD88 e TRIF. Além disso, observamos que CD200 pode ser induzida pelo DNA do parasito, assim como por vesículas extracelulares (VEs) contendo DNA liberadas por ele. Os resultados in vivo mostraram que a ausência de TLR9 não altera o tamanho da lesão e nem a expressão de CD200 nos macrófagos presentes. Contudo, a carga parasitária foi maior nos camundongos selvagens. A partir dos resultados obtidos podemos concluir que a L. (L.) amazonensis induz CD200 de maneira dependente da via de TLRs e que esta indução pode ser estimulada pelo DNA do parasito. / L. (L.) amazonensis evades the immune response of host macrophage inducing the CD200 expression in the cell. However, it is not yet known how this mechanism occurs. The objective of this work was to evaluate the participation of TLRs in CD200 induction in infected macrophages by L. (L.) amazonensis. The results showed that the CD200 induction by the parasite is dependent on TLR9 and the adaptor proteins MyD88 and TRIF. In addition, we observed that the CD200 can be induced by the parasite DNA, as well as by extracellular vesicles (EVs) containing DNA released by it. In vivo results showed that the absence of TLR9 does not alter the lesion size nor the CD200 expression in macrophages present in the lesion. However, the parasite load was higher in wild type mice. Therefore, we can conclude that the CD200 induction by L. (L.) amazonensis amastigotes is TLR dependent and this can be stimulated by the parasite DNA.

A l’instar du lymphome de Burkitt (LB) avec la translocation de MYC, les lymphomes diffus à grandes cellules B (DLBCL) par d'autres mécanismes (mutation, amplification, dérégulation du promoteur) sont associés à une dérégulation de c-Myc, facteur de transcription maitre de la prolifération. Les DLBCL sont classés en deux sous-groupes: « centre germinatif » (GCB) et « cellule B activée » (ABC) avec activation constitutive de NF-κB. Cette activation constitutive de NF-κB peut être le résultat d'altérations génétiques (MYD88, A20, TRAF2 et TRAF5) ou de l'activation du BCR ou CD40. Ces caractéristiques soulèvent la question de la synergie d’action entre NF-κB et c-Myc dans les ABC-DLBCL. Nous avons analysé l’effet d'une activation continue de c-Myc dans un contexte de sur-activation de NF-κB par plusieurs inducteurs. Nos résultats montrent que la surexpression de c-Myc dans un contexte d'induction de NF-κB, i) par le programme EBV latence III, apporte un avantage sélectif à ces cellules (expression génique en faveur d'un métabolisme élevé, prolifération intense et protection contre apoptose), ii) par le TLR9 (modèle in vivo et in vitro), augmente la survie et la prolifération des lymphocytes B des souris λc-Myc (augmentation des cellules B activées, splénomégalie, augmentation de la prolifération des lymphocytes B, modification du microenvironnement tumoral), et iii) par CD40, induit une lymphomagenèse B très agressive dans les souris doubles transgéniques CD40/Myc, les tumeurs ont un phénotype proche des ABC-DLBCL. Ces résultats suggèrent que c-Myc est un événement co-transformant dans les lymphomes agressifs avec un phénotype activé par NF-κB, tel que les ABC-DLBCL. / Not only Burkitt lymphoma (BL) with the translocation of MYC, but also diffuse large B-cell lymphoma (DLBCL) by other mechanisms (mutation, amplification, promoter dysregulation…) are associated with dysregulation of c-Myc, the master transcription factor for proliferation. DLBCL’s are classified in two subgroups: “Germinal center B-cell” (GCB) without and “activated B-cell” (ABC) with constitutive NF-κB activation. This constitutive activation of NF-κB can be the result of genetic alterations (MYD88, A20, TRAF2, and TRAF5) or the activation of B-cell receptor or CD40. These features raise the question of the synergy of action between NF-κB and c-Myc in ABC-DLBCL. We analyzed the effect of a continuous activation of c-Myc in a context of over-activation of NF-κB by several inductors. Our results show that overexpression of c-Myc in the context of induction of NF-κB, i) by EBV latency III program, provides a selective advantage to those cells (gene expression in favor of a high metabolism, intense proliferation and protection against apoptosis), ii) by TLR9 (in vivo and in vitro model) increases the survival and proliferation of B lymphocytes of λc-Myc mice (increase of activated B cells, splenomegaly, increased B cells proliferation, modification of tumor microenvironment), and iii) by CD40, induces a very aggressive B lymphomagenesis in CD40/Myc double transgenic mice, the tumors have a phenotype close to ABC-DLBCL. These results suggest that c-Myc is an NF-κB co-transforming event in aggressive lymphomas with an activated phenotype by NF-κB, such as ABC-DLBCL.