Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA270499 | ENA |
REPOSITORIES: ENA
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Project description:The malignant cells of Hodgkin's lymphoma are characterized by a constitutive activation of the canonical as well as the non-canonical NF-κB signaling cascades. We carried out genome-wide localization and expression profiling experiments in the Hodgkin lymphoma cell line L1236 for the canonical and non-canonical NF-κB pathway components p65, p50 and p52, RelB, respectively. We found that the single NF-κB subunits bind to overlapping, but distinct cistromes by using consensus motifs of high similarity.
2016-02-18 | GSE63736 | GEO
Project description:Mesenchymal stem cells (MSCs) are known to induce the conversion of activated T-cells into regulatory T-cells in vitro. The marker CD69 is a target of canonical NF-κB signaling and is transiently expressed upon activation; however, stable CD69 expression defines cells with immunoregulatory properties. Given its enormous therapeutic potential, we explored the molecular mechanisms underlying the induction of regulatory cells by MSCs. Peripheral blood CD3+ T-cells were activated and cultured in the presence or absence of MSCs. CD4+ cell mRNA expression was then characterized by microarray analysis. The drug BAY11-7082 and a siRNA against RELB were used to explore the differential roles of canonical and non-canonical NF-κB signaling, respectively. Flow cytometry and real-time PCR were used for analyses. Genes with immunoregulatory functions, CD69 and non-canonical NF-κB subunits (RELB and NFKB2) were all expressed at higher levels in lymphocytes co-cultured with MSCs. The frequency of CD69+ cells among lymphocytes cultured alone progressively decreased after activation. In contrast, the frequency of CD69+ cells increased significantly following activation in lymphocytes co-cultured with MSCs. Inhibition of canonical NF-κB signaling by BAY immediately following activation blocked the induction of CD69; however, inhibition of canonical NF-κB signaling on the 3rd day further induced the expression of CD69. Furthermore, late expression of CD69 was inhibited by RELB siRNA. These results indicate that the canonical NF-κB pathway controls the early expression of CD69 after activation; however, in an immunoregulatory context, late and sustained CD69 expression is promoted by the non-canonical pathway and is inhibited by canonical NF-κB signaling. In order to study the molecular basis by which Multipotent Mesenchymal Stromal/Stem Cells (MSC) exert their immune regulatory function, immunomagnetically purified CD3+ T-cells from the peripheral blood of 3 individuals were activated and cultured in the presence or absence of MSCs. Following 5 days, CD4+ and CD8+ T-cells were further immunomagnetically selected and their gene expression profiles were obtained by microarrays and compared. Paired samples from 3 individuals were used for this analysis.
2011-08-02 | E-GEOD-31153 | biostudies-arrayexpress
Project description:Aberrant activation of NF-κB transcription factors is a hallmark of human lymphoma. Many lymphoma- as well as microenvironment-associated alterations mediating enhanced NF-κB signaling occur upstream of the IκB Kinase complex and its key kinase IKK2, therefore affecting additional pathways. Here, we specifically investigated the effects of graded canonical NF-κB activation in mouse B cells, induced through the expression of one or two copies of a constitutively active IKK2 variant (IKK2ca). Strong canonical NF-κB signaling drives an early expansion of B1a cells, culminating in lethal lymphomagenesis with complete penetrance. These B cell malignancies resemble human small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL) with respect to disease course, gene expression and stereotypic B cell receptor clonality. Mice with less pronounced canonical NF-κB activation presented delayed, more heterogeneous lymphomagenesis with lower penetrance, highlighting NF-κB dose-dependent effects. Mechanistically, we show that constitutive IKK2 signals provide a profound cell-intrinsic competitive advantage to B1a cells and strongly synergize with TCL1 overexpression, resulting in a severely accelerated and aggravated CLL-like disease. In addition, strong constitutive NF-κB activation overcomes the critical dependency of TC1tg lymphoma cells on obligate environmental maintenance signals. In conclusion, we provide direct in vivo proof for canonical NF-κB signals as an oncogenic driver in an animal model, and demonstrate reduced tumor microenvironment dependency as a key NF-κB-mediated mechanism in lymphomagenesis. Our findings underscore the pivotal role of this pathway in human SLL/CLL and its potential as a therapeutic target, particularly for aggressive/refractory disease.
2026-03-11 | GSE289016 | GEO
Project description:Aberrant activation of NF-κB transcription factors is a hallmark of human lymphoma. Many lymphoma- as well as microenvironment-associated alterations mediating enhanced NF-κB signaling occur upstream of the IκB Kinase complex and its key kinase IKK2, therefore affecting additional pathways. Here, we specifically investigated the effects of graded canonical NF-κB activation in mouse B cells, induced through the expression of one or two copies of a constitutively active IKK2 variant (IKK2ca). Strong canonical NF-κB signaling drives an early expansion of B1a cells, culminating in lethal lymphomagenesis with complete penetrance. These B cell malignancies resemble human small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL) with respect to disease course, gene expression and stereotypic B cell receptor clonality. Mice with less pronounced canonical NF-κB activation presented delayed, more heterogeneous lymphomagenesis with lower penetrance, highlighting NF-κB dose-dependent effects. Mechanistically, we show that constitutive IKK2 signals provide a profound cell-intrinsic competitive advantage to B1a cells and strongly synergize with TCL1 overexpression, resulting in a severely accelerated and aggravated CLL-like disease. In addition, strong constitutive NF-κB activation overcomes the critical dependency of TC1tg lymphoma cells on obligate environmental maintenance signals. In conclusion, we provide direct in vivo proof for canonical NF-κB signals as an oncogenic driver in an animal model, and demonstrate reduced tumor microenvironment dependency as a key NF-κB-mediated mechanism in lymphomagenesis. Our findings underscore the pivotal role of this pathway in human SLL/CLL and its potential as a therapeutic target, particularly for aggressive/refractory disease.
2026-03-11 | GSE289013 | GEO
Project description:Persistent activation of canonical and non-canonical NF-κB pathways is a hallmark of the malignant Hodgkin and Reed-Sternberg cells in classical Hodgkin lymphoma (cHL). We identified lymphotoxin alpha (LTA), which is secreted by the cHL cell line L-1236 in high concentrations. This cytokine contributes to the constitutive activation of the canonical and non-canonical NF-κB pathways. L-1236 cells were purchased from the DSMZ (Braunschweig, Germany) and cultured in RPMI (Gibco) with 10% heat-inactivated fetal calf serum (FCS; Gibco). Cells were transducted with the lentiCRIPSPR v2 vector containing gRNAs which target the second (g2) and the fourth exon (g3) of LTA. Following single cell clonal selection, L-1236 control cells (v2) and two LTA knockout (KO) clones g2_1 and g3_4 were cultured in normal culture medium for 72 h. The RNA was extracted using the RNeasy kit (Qiagen) according to manufacturer’s instructions. Preparation of cDNA, fragmentation and labeling was performed with the GeneChIPTM WT PLUS reagent kit (ThermoFisher Scientific). Samples were hybridized to the human Clariom™ S Assay (ThermoFisher Scientific).
2019-01-24 | E-MTAB-6896 | biostudies-arrayexpress
Project description:Gene expression profile of the NF-κB subunit p52 in Hodgkin’s lymphoma
| PRJNA270498 | ENA
Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, we identify NIK as a critical negative regulator of beta cell function as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the non-canonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity. To uncover the role of NIK in pancreatic beta cells, we performed a gene expression microarray analysis comparing pancreatic islets with constitutive beta cell intrinsicNIK activation from the 16 week old mice (beta cell specific TRAF2 and TRAF2 knockout mice) to their controls (n=3 per group).
2015-06-18 | E-GEOD-68317 | biostudies-arrayexpress
Project description:The malignant cells of Hodgkin's lymphoma are characterized by a constitutive activation of the canonical as well as the non-canonical NF-κB signaling cascades. We carried out genome-wide localization and expression profiling experiments in the Hodgkin lymphoma cell line L1236 for the canonical and non-canonical NF-κB pathway components p65, p50 and p52, RelB, respectively. We found that the single NF-κB subunits bind to overlapping, but distinct cistromes by using consensus motifs of high similarity. ChIP-Seq analysis of 4 NF-κB subunits with 2 biological replicates each
2016-02-18 | E-GEOD-63736 | biostudies-arrayexpress
Project description:Mesenchymal stem cells (MSCs) are known to induce the conversion of activated T-cells into regulatory T-cells in vitro. The marker CD69 is a target of canonical NF-κB signaling and is transiently expressed upon activation; however, stable CD69 expression defines cells with immunoregulatory properties. Given its enormous therapeutic potential, we explored the molecular mechanisms underlying the induction of regulatory cells by MSCs. Peripheral blood CD3+ T-cells were activated and cultured in the presence or absence of MSCs. CD4+ cell mRNA expression was then characterized by microarray analysis. The drug BAY11-7082 and a siRNA against RELB were used to explore the differential roles of canonical and non-canonical NF-κB signaling, respectively. Flow cytometry and real-time PCR were used for analyses. Genes with immunoregulatory functions, CD69 and non-canonical NF-κB subunits (RELB and NFKB2) were all expressed at higher levels in lymphocytes co-cultured with MSCs. The frequency of CD69+ cells among lymphocytes cultured alone progressively decreased after activation. In contrast, the frequency of CD69+ cells increased significantly following activation in lymphocytes co-cultured with MSCs. Inhibition of canonical NF-κB signaling by BAY immediately following activation blocked the induction of CD69; however, inhibition of canonical NF-κB signaling on the 3rd day further induced the expression of CD69. Furthermore, late expression of CD69 was inhibited by RELB siRNA. These results indicate that the canonical NF-κB pathway controls the early expression of CD69 after activation; however, in an immunoregulatory context, late and sustained CD69 expression is promoted by the non-canonical pathway and is inhibited by canonical NF-κB signaling.
2011-08-03 | GSE31153 | GEO
Project description:Malignant cells of Hodgkin's lymphoma (HL) cells are characterized by constitutive activation of the canonical as well as the non-canonical NF-κB signaling cascades. Knockdown of a subunit combination corresponding to the non-canonical NF-κB dimer (p52/RelB) in the HL cell line L-1236 caused up-regulation of a set of genes that are associated with hematopoietic and lymphoid organ development. As p52 can form homodimeric complexes, which can repress transcription either alone or in association with transcriptional repressors such as HDAC1, we knocked down p52 alone to analyze its role in gene repression in HL cells. We found that the single knockdown of p52 is indeed sufficient to up-regulate an interesting set of genes that may play a role in B-cell and/or HL development.
2016-12-21 | GSE64234 | GEO