Germinal center B cell maintenance and differentiation are controlled by distinct NF-κB transcription factor subunits

Heise, Nicole; Silva, Nilushi S. De; Silva, Kathryn; Carette, Amanda; Simonetti, Giorgia; Pasparakis, Manolis; Klein, Ulf

doi:10.1084/jem.20132613

Cited by 190 publications

(256 citation statements)

References 59 publications

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“…by guest www.bloodjournal.org From et al determined that CREL is specifically associated with failure to activate a metabolic program that promotes cell growth after the formation of dark and light zones in the GC reaction. 47 Because metabolic programs that promote cell growth present an important criteria to cell division, and inhibition of these programs arrest cell growth and lead to cell death, our results on CREL are in agreement with their findings. Furthermore, the temporal dependence on CREL activity coincides with a post-centroblasts GC development stage that is associated with the ABC-like DLBCL cell-of-origin developmental stage and with a significant decrease in basal miR-181a expression.…”

Section: Discussionsupporting

confidence: 91%

miR-181a negatively regulates NF-κB signaling and affects activated B-cell–like diffuse large B-cell lymphoma pathogenesis

Kozloski¹,

Jiang²,

Bhatt

et al. 2016

Blood

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• miR-181a regulates the NF-kB signaling pathway by targeting CARD11, NFKBIA, NFKB1, RELA/P65, and REL.• miR-181a represses NF-kB signaling and decreases cell proliferation and survival most potently in the NF-kB dependent ABC-DLBCL subgroup.Distinct subgroups of diffuse large B-cell lymphoma (DLBCL) genetically resemble specific mature B-cell populations that are blocked at different stages of the immune response in germinal centers (GCs). The activated B-cell (ABC)-like subgroup resembles post-GC plasmablasts undergoing constitutive survival signaling, yet knowledge of the mechanisms that negatively regulate this oncogenic signaling remains incomplete. In this study, we report that microRNA (miR)-181a is a negative regulator of nuclear factor k-light-chain enhancer of activated B-cells (NF-kB) signaling. miR-181a overexpression significantly decreases the expression and activity of key NF-kB signaling components. Moreover, miR181a decreases DLBCL tumor cell proliferation and survival, and anti-miR-181a abrogates these effects. Remarkably, these effects are augmented in the NF-kB dependent ABC-like subgroup compared with the GC B-cell (GCB)-like DLBCL subgroup. Concordantly, in vivo analyses of miR-181a induction in xenografts results in slower tumor growth rate and prolonged survival in the ABC-like DLBCL xenografts compared with the GCB-like DLBCL. We link these outcomes to relatively lower endogenous miR-181a expression and to NF-kB signaling dependency in the ABC-like DLBCL subgroup. Our findings indicate that miR-181a inhibits NF-kB activity, and that manipulation of miR-181a expression in the ABC-like DLBCL genetic background may result in a significant change in the proliferation and survival phenotype of this malignancy. (Blood. 2016;127(23):2856-2866

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Section: Discussionsupporting

confidence: 91%

miR-181a negatively regulates NF-κB signaling and affects activated B-cell–like diffuse large B-cell lymphoma pathogenesis

Kozloski¹,

Jiang²,

Bhatt

et al. 2016

Blood

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“…By contrast, bone marrow-derived pHSCs give rise to shorter-lived BIb cells, which have homing properties that are similar to BIa cells. Most importantly, bone marrow develops BII-type B lymphocytes, which organize the B cell follicles in spleen and lymph nodes (85,86 Any high-affinity, autoreactive B cells that emerge as accidental products of the hypermutation process during this affinity maturation of better-fitting antibodies should be silenced and eliminated to avoid autoimmune disease (89)(90)(91)(92). Again, the microenvironments mediating this postulated negative selection of autoantibodies need further investigation.…”

Section: Establishment Of Peripheral Pools Of Mature B Cellsmentioning

confidence: 99%

Checkpoints that control B cell development

2015

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“…The classical nuclear factor kappa B (NF-jB) pathway consists of three subunits, cRel, RelA and p50, forming two major heterodimers, cRel/p50 and RelA/p50 [76]. Both cRel and RelA are induced transiently upon BCR ligation, peaking 1-2 h after stimulation [77].…”

Section: Nf-jbmentioning

confidence: 99%

“…Thus, BCR selection and resultant cRel activation appears to drive the affinity maturation process. Unlike cRel, RelA-ablation has no impact upon GC maintenance, but results instead in a significant reduction in the prevalence of PCs and a subsequent loss in IgG serum titres through impaired up-regulation of BLIMP1 [76]. cMyc cMyc is a global driver of cell growth and division.…”

Section: Molecular and Cellular Aspects Of B Cell Biology Review Seriesmentioning

confidence: 99%

Transcription factors regulating B cell fate in the germinal centre

Recaldin

Fear

2015

Clinical and Experimental Immunology

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SummaryDiversification of the antibody repertoire is essential for the normal operation of the vertebrate adaptive immune system. Following antigen encounter, B cells are activated, proliferate rapidly and undergo two diversification events; somatic hypermutation (followed by selection), which enhances the affinity of the antibody for its cognate antigen, and classswitch recombination, which alters the effector functions of the antibody to adapt the response to the challenge faced. B cells must then differentiate into antibody-secreting plasma cells or long-lived memory B cells. These activities take place in specialized immunological environments called germinal centres, usually located in the secondary lymphoid organs. To complete the germinal centre activities successfully, a B cell adopts a transcriptional programme that allows it to migrate to specific sites within the germinal centre, proliferate, modify its DNA recombination and repair pathways, alter its apoptotic potential and finally undergo terminal differentiation. To co-ordinate these processes, B cells employ a number of 'master regulator' transcription factors which mediate wholesale transcriptomic changes. These master transcription factors are mutually antagonistic and form a complex regulatory network to maintain distinct gene expression programs. Within this network, multiple points of positive and negative feedback ensure the expression of the 'master regulators', augmented by a number of 'secondary' factors that reinforce these networks and sense the progress of the immune response. In this review we will discuss the different activities B cells must undertake to mount a successful T cell-dependent immune response and describe how a regulatory network of transcription factors controls these processes.

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Germinal center B cell maintenance and differentiation are controlled by distinct NF-κB transcription factor subunits

Cited by 190 publications

References 59 publications

miR-181a negatively regulates NF-κB signaling and affects activated B-cell–like diffuse large B-cell lymphoma pathogenesis

miR-181a negatively regulates NF-κB signaling and affects activated B-cell–like diffuse large B-cell lymphoma pathogenesis

Checkpoints that control B cell development

Transcription factors regulating B cell fate in the germinal centre

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