Repression of B-Cell Linker (BLNK) and B-Cell Adaptor for Phosphoinositide 3-Kinase (BCAP) Is Important for Lymphocyte Transformation by Rel Proteins

Gupta, Nupur; Delrow, Jeffrey J.; Drawid, Amar; Sengupta, Anirvan M.; Fan, Guang; Gélinas, Céline

doi:10.1158/0008-5472.can-07-3169

Cited by 16 publications

(23 citation statements)

References 62 publications

(82 reference statements)

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“…However, as previous studies suggest that TNFRSF14 aberrations may confer a poor prognosis in patients treated with chemoimmunotherapy, 4 it is likely that additional or alternative HVEM-mediated mechanisms impact on FL B-cell survival in the autologous setting. As BTLA is also expressed on B cells, and negatively regulates B-lymphocyte transformation and malignant B-cell survival, [35][36][37] reduction of HVEM ligation of BTLA on FL B cells either in cis or trans (from neighboring tumor cells) could potentiate tumor growth and survival in this setting.…”

Section: Discussionmentioning

confidence: 99%

TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses

Kotsiou

Okosun

Besley

et al. 2016

Blood

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Key Points• TNFRSF14 gene aberrations, common in FL, increase the ability of lymphoma cells to stimulate allogeneic T-cell responses.• TNFRSF14 lesions were associated with increased acute GVHD supporting stratified transplantation approaches in the allogeneic setting.Donor T-cell immune responses can eradicate lymphomas after allogeneic hematopoietic stem cell transplantation (AHSCT), but can also damage healthy tissues resulting in harmful graftversus-host disease (GVHD). Next-generation sequencing has recently identified many new genetic lesions in follicular lymphoma (FL). One such gene, tumor necrosis factor receptor superfamily 14 (TNFRSF14), abnormal in 40% of FL patients, encodes the herpes virus entry mediator (HVEM) which limits T-cell activation via ligation of the B-and T-lymphocyte attenuator.As lymphoma B cells can act as antigen-presenting cells, we hypothesized that TNFRSF14 aberrations that reduce HVEM expression could alter the capacity of FL B cells to stimulate allogeneic T-cell responses and impact the outcome of AHSCT. In an in vitro model of alloreactivity, human lymphoma B cells with TNFRSF14 aberrations had reduced HVEM expression and greater alloantigen-presenting capacity than wild-type lymphoma B cells. The increased immune-stimulatory capacity of lymphoma B cells with TNFRSF14 aberrations had clinical relevance, associating with higher incidence of acute GVHD in patients undergoing AHSCT. FL patients with TNFRSF14 aberrations may benefit from more aggressive immunosuppression to reduce harmful GVHD after transplantation. Importantly, this study is the first to demonstrate the impact of an acquired genetic lesion on the capacity of tumor cells to stimulate allogeneic T-cell immune responses which may have wider consequences for adoptive immunotherapy strategies. (Blood. 2016;128(1):72-81)

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Section: Discussionmentioning

confidence: 99%

TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses

Kotsiou

Okosun

Besley

et al. 2016

Blood

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“…D, Western blots for PU.1, CD10, and ␤-tubulin were compared in BJAB cells expressing an shRNA directed against PU.1 or a scrambled shRNA (con) that does not recognize any human sequence (negative control). E, whole cell extracts were made from DT40 and DT40-v-Rel cells (18), and anti-v-Rel Western blotting was performed (left panel); a v-Rel-transformed chicken spleen cell line served as the positive control. In the right panel, PU.1 and GAPDH transcript levels were analyzed by RT-PCR.…”

Section: Discussionmentioning

confidence: 99%

“…Cell Culture, DNA Constructs, and Stable Cell Line Generation-Human A293, A293T, Bosc23, BJAB, SUDHL-4, BL41, Daudi, IB4, RC-K8, and chicken DT40 cells (gift of Cé-line Gélinas) (18), were grown in Dulbecco's modified Eagle's medium (DMEM) (Invitrogen) supplemented with either 10 or 20% heat-inactivated fetal bovine serum (FBS) (Biologos) as described (19). The six human B-lymphoma cell lines used in this study are as follows: BJAB, EBV-negative, GCB-like DLBCL (20,21); SUDHL-4, a B-lymphoma that has been characterized as both a follicular lymophoma (22) and GCBlike DLBCL (23); BL-41, EBV-negative Burkitt lymphoma (14); Daudi, EBV-positive, LMP1-negative Burkitt lymphoma (24); IB4, EBV-transformed lymphoblastoid cell line (14); and RC-K8, ABC-like DLBCL (25).…”

Section: Methodsmentioning

confidence: 99%

NF-κB Down-regulates Expression of the B-lymphoma Marker CD10 through a miR-155/PU.1 Pathway

Thompson¹,

Herscovitch²,

Zhao

et al. 2011

Journal of Biological Chemistry

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The NF-B signaling pathway is misregulated in a variety of human diseases including many chronic inflammatory diseases and cancers. As such, an understanding of the molecular details of NF-B-dependent gene networks has implications for improved disease diagnoses and therapies. CD10, also known as the common acute lymphocytic leukemia antigen (CALLA) or neutral endopeptidase, is a cellsurface zinc metalloendopeptidase (1, 2). The ability of CD10 to cleave signal peptides at the cell surface can affect cell proliferation, differentiation, and migration (2-4). Expression of CD10 can be used as a diagnostic marker for a variety of cancers (5-9). Relevant to this study, CD10 is highly expressed in the germinal center B-cell (GCB) 6 molecular subtype of diffuse large B-cell lymphoma (DLBCL), whereas CD10 expression is low in the activated B-cell (ABC) subtype of DLBCL (8, 9). ABC DLBCLs also have a high NF-B gene expression profile and a poorer clinical prognosis as compared with GCB DLBCLs (10). As such, reduced expression of CD10 and high NF-B activity are both correlated with a less favorable DLBCL patient outcome (10 -12).The correlation between high NF-B activity and reduced CD10 expression has been observed in several other settings as well. We previously showed that overexpression of an activated mutant of the NF-B family transcription factor REL in the GCB-like B-lymphoma cell line BJAB leads to reduced expression of CD10 (13). Infection of cells with Epstein-Barr virus (EBV) or human cytomegalovirus, both inducers of NF-B, causes reduced expression of CD10 (14, 15). Taken together, such results suggested to us that NF-B or a target of NF-B is involved in repressing CD10 gene/protein expression in certain B-cell lymphomas.Little is known about the control of CD10 transcription. Sequence analysis of the CD10 promoter/enhancer region revealed the presence of three consensus binding sites for transcription factor PU.1 (16). PU.1 is a member of the Ets family of transcription factors and is required for proper Bcell development and differentiation (17). Additionally, increased PU.1 expression has been correlated with the GCB subtype of DLBCL (8). Therefore, we were interested in investigating whether PU.1 contributes to the regulation of CD10 expression in B-cell lymphoma.In this report, we provide evidence for a functional link between activation of NF-B and reduced expression of CD10. We show that activation of NF-B in the GCB-like DLBCL cell line BJAB leads to reduced CD10 expression. Our data are consistent with a pathway in which NF-B-induced up-regulation of micro-RNA miR-155 leads to down-regulation of PU.1 protein levels, and consequently, reduced levels of * This work was supported, in whole or in part, by National Institutes of Health Grant CA047763 and American Recovery and Reinvestment Act of 2009 supplement Grant CA047763021S3 (to T. D. G.). □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Fig. S1

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“…While RelA failed to transform chicken lymphoid cells on its own, replacement of RelA's TAD with that of either v-Rel or c-Rel conferred a strong transforming phenotype both in vitro and in vivo (13). Recent work showed that in addition to activating expression of antiapoptotic and proproliferative genes, the Rel TADs can also lead to gene-specific transcriptional repression of genes such as those for SH3BGRL and the B-cell receptor signaling molecules BCAP and BLNK, and this activity is as important for lymphocyte transformation by v-Rel as is its transactivation function (19,35). Additionally v-Rel can promote expression and alternative splicing of telomerase reverse transcriptase (TERT), which is also involved in lymphocyte transformation (24).…”

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confidence: 99%

“…The 293T human embryonic kidney cell line, primary chicken embryo fibroblasts (CEFs), v-Rel-transformed chicken spleen cells (CSC), and the DT40 chicken pre-B-cell line were cultured as described previously (12,19). Luciferase assays were performed with extracts from 293T cells (1 ϫ 10 6 ) transfected with calcium phosphate using a total of 6.01 g DNA, including 0.01 g of hRL-null Renilla luciferase DNA as a control, as described previously (12).…”

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confidence: 99%

CAPERα Is a Novel Rel-TAD-Interacting Factor That Inhibits Lymphocyte Transformation by the Potent Rel/NF-κB Oncoprotein v-Rel

Dutta

Fan

Gélinas

2008

J Virol

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The Rel/NF-B family of transcription factors is key for immune and inflammatory responses and also controls cell proliferation and apoptosis. The v-Rel oncoprotein of reticuloendotheliosis virus strain T (Rev-T) is the most potent oncogenic member of this family. Both v-Rel and its cellular homologue c-Rel transform primary splenic lymphocytes in vitro and cause fatal leukemia/lymphomas in chickens and transgenic mice (5,9,17,22,23,33,38,39). This agrees with the implication of Rel/NF-B in the pathogenesis and chemoresistance of many hematopoietic and solid tumors, including primary mediastinal B-cell lymphomas (PMBCL) and classical Hodgkin's lymphoma, in which constitutively high levels of nuclear c-Rel protein are necessary for tumor cell survival and proliferation (3,4,14,18,20,27,49). Additionally, some PMBCL and follicular lymphomas harbor c-rel gene mutations that decrease c-Rel's transactivation potency and enhance its transforming activity in primary chicken lymphocytes (45). This is consistent with the increased transforming phenotype conferred by certain mutations in v-Rel and c-Rel and indicates that modulation of Rel's transcriptional activity can significantly affect its oncogenicity (12,43,44).The Rel proteins bind to B DNA sites as homo-or heterodimers with other NF-B family members via their N-terminal Rel homology domain (RHD), which also mediates nuclear localization and association with inhibitory IB subunits.

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Repression of B-Cell Linker (BLNK) and B-Cell Adaptor for Phosphoinositide 3-Kinase (BCAP) Is Important for Lymphocyte Transformation by Rel Proteins

Cited by 16 publications

References 62 publications

TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses

TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses

NF-κB Down-regulates Expression of the B-lymphoma Marker CD10 through a miR-155/PU.1 Pathway

CAPERα Is a Novel Rel-TAD-Interacting Factor That Inhibits Lymphocyte Transformation by the Potent Rel/NF-κB Oncoprotein v-Rel

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