Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA119303 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:<p>Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression, and rational therapy design. Here, we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-kB pathway in a total of 41% of cases including CYLD, TRAF3, NFKBIA and NLRC5. Functional analysis confirmed novel inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent member protein 1 (LMP1) functions to constitutively activate NF-kB signaling, and we observed mutual exclusivity among somatic NF-kB pathway aberrations and LMP1-overexpression, suggesting that NF-kB activation is selected for by both somatic and viral events during NPC pathogenesis.</p>
| phs001244 | dbGaP
Project description:Mechanisms of constitutive NF-kappaB signaling in multiple myeloma are unknown. An inhibitor of IkappaB kinase beta (IKKbeta), targeting the classical NF-kappaB pathway, was lethal to many myeloma cell lines. Several had elevated expression of NIK due to genomic alterations or enhanced protein stability while others had inactivating mutations or deletion of TRAF3. Both abnormalities triggered the classical and alternative NF-kappaB pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-kappaB target gene expression, often associated with genetic and epigenetic alteration of NIK, TRAF3, CYLD, BIRC2/BIRC3, CD40, NFKB1, and NFKB2. These genetic and functional data demonstrate that addiction to the NF-kappaB pathway is a frequent feature of myeloma and suggest that IKKbeta inhibitors hold promise for the treatment of this disease. Keywords: time series design
2007-10-29 | GSE8477 | GEO
Project description:Mechanisms of constitutive NF-kappaB signaling in multiple myeloma are unknown. An inhibitor of IkappaB kinase beta (IKKbeta), targeting the classical NF-kappaB pathway, was lethal to many myeloma cell lines. Several had elevated expression of NIK due to genomic alterations or enhanced protein stability while others had inactivating mutations or deletion of TRAF3. Both abnormalities triggered the classical and alternative NF-kappaB pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-kappaB target gene expression, often associated with genetic and epigenetic alteration of NIK, TRAF3, CYLD, BIRC2/BIRC3, CD40, NFKB1, and NFKB2. These genetic and functional data demonstrate that addiction to the NF-kappaB pathway is a frequent feature of myeloma and suggest that IKKbeta inhibitors hold promise for the treatment of this disease. Keywords: time series design
2007-10-29 | GSE8476 | GEO
Project description:NF-kB pathway activation is the hallmark of hematological malignancies. In multiple myeloma (MM), a large variety of genomic alterations leading to either inactivation of repressor such as TRAF3, CYLD or cIAP1/2 or amplification of activators such as CD40 or NIK collectively contribute to frequently deregulate NF-kB signaling. In order to evaluate the prognostic impact of NF-kB mutations in MM, we performed a comprehensive analysis of a panel of newly diagnosed patients with cIAP1/2 biallelic deletion. We found that all patients have dysregulated NF-kB pathway and the majority of them presented t(4;14). Then we analyzed clinical outcome of 37 MM at presentation with t(4;14) and treated with bortezomib according to their NF-kB status. We showed that increase of NF-kB activity confers prolonged event-free survival. Altogether, our data suggest that NF-kB activation resulting from NF-kB mutations (ie cIAP1/2 deletion) or other mechanisms improves outcome of t(4;14)-positive MM treated with bortezomib.
2015-09-15 | GSE31272 | GEO
Project description:Chronic NF-kB activation in inflammation and cancer has long been linked to persistent activation of NF-kB–responsive gene promoters. However, NF-kB factors also massively bind to gene bodies. Here, we demonstrate that recruitment of the NF-kB factor RELA to intragenic regions regulates alternative splicing upon NF-kB activation by the viral oncogene Tax of HTLV-1. Integrative analyses of RNA splicing and chromatin occupancy, combined with chromatin tethering assays, demonstrate that DNA-bound RELA interacts with and recruits the splicing regulator DDX17, in an NF-kB activation–dependent manner. This leads to alternative splicing of target exons due to the RNA helicase activity of DDX17. Similar results were obtained upon Tax-independent NF-kB activation, indicating that Tax likely exacerbates a physiological process where RELA provides splice target specificity. Collectively, our results demonstrate a physical and direct involvement of NF-kB in alternative splicing regulation, which significantly revisits our knowledge of HTLV-1 pathogenesis and other NF-kB–related diseases.
2020-05-12 | GSE123752 | GEO
Project description:As multiple myeloma tumors universally dysregulate cyclin D genes we conducted high-throughput chemical library screens for compounds that induce suppression of cyclin D2. The top-ranked compound was a natural triterpenoid, pristimerin. We used gene expression microarray studies to identify co-regulated pristimerin-response genes and to deduce the compound’s direct molecular target(s), utilizing pattern-matching algorithms available at the Connectivity Map (Cmap). The early transcriptional response of cells treated with pristimerin closely resembles cellular responses elicited by proteosome inhibitors, with rapid induction of heat shock proteins, activating transcription factor (ATF) 3 and CHOP. Enzymatic assays and immunoblotting confirm that pristimerin rapidly (<90min) and specifically inhibits chymotrypsin-like proteosome activity at low concentrations (<100nM) and causes accumulation of cellular ubiquitinated proteins. Notably, cytotoxic triterpenoids including pristimerin inhibit NF-kB activation via inhibition of IKKa or IKKb while proteosome inhibitors instead suppress NF-kB function by impairing degradation of ubiquitinated-IkB. By inhibiting both IKK and the proteosome pristimerin causes overt suppression of constitutive NF-kB activity in myeloma cells that may mediate its suppression of cyclin D. Multiple myeloma is exquisitely sensitive to proteosome or NF-kB pathway inhibition. Consistent with this, pristimerin is potently and selectively lethal to primary myeloma cells (IC50<100nM), inhibits xenografted plasmacytoma tumors in mice and is synergistically cytotoxic with bortezomib – providing the rationale for pharmaceutical development of triterpenoid dual-function proteosome/NF-kB inhibitors as therapeutics for human multiple myeloma and related malignancies. Keywords: small molecule drug response, stress response
2008-12-18 | GSE14011 | GEO
Project description:Compensatory IKKa activation of classical NF-kB signaling during IKKb inhibition
| PRJNA105739 | ENA
Project description:Background: Constitutive activation of the alternative NF-?B pathway leads to marginal zone B cell expansion and disorganized spleen microarchitecture. Furthermore, uncontrolled alternative NF-?B signaling results in the development and progression of cancer. We aimed here to learn about the mechanisms how does the constitutively active alternative NF-?B pathway exert its effects in these malignant processes. Methodology/Principal Findings: To explore the consequences of constitutive alternative NF-?B activation on genome-wide transcription, we compared gene expression profiles of wild-type and NF-kB2/p100-deficient (p100-/-) primary mouse embryonic fibroblasts (MEFs) and spleens. Microarray experiments revealed 73 differentially regulated genes in p100-/- vs. wild-type MEFs. Chromatin immunoprecipitation (ChIP) assays showed in p100-/- MEFs direct binding of RelB and p52 to the promoter of the enpp2 gene encoding Enpp2/Autotaxin, a protein with an important role in lymphocyte homing and cell migration. Gene ontology analysis revealed upregulation of genes with anti-apoptotic/proliferative activity (enpp2, serpina3g, traf1, rrad), chemotactic/locomotory activity (enpp2, ccl8), and lymphocyte homing activity (enpp2, cd34). Most importantly, biochemical analyses of MEFs and gene expression analyses of mice indicated a crosstalk between classical and alternative NF-?B pathways. Conclusions/Significance: The present results show that uncontrolled alternative NF-?B signaling is further enhanced by classical NF-?B activation, indicating that p100 deficiency alone is insufficient for full induction of a subset of genes by the alternative NF-?B pathway. cell type comparison (wt vs p100-/-) after genetic modification
2012-12-21 | E-GEOD-30317 | biostudies-arrayexpress
Project description:IT848 is a small molecule inhibiting DNA binding of all five NF-kB subunits. In vitro treatment of lymphoma or multiple myeloma cells with IT848 suppresses NF-kB transcriptional activity, cell growth, and indices apoptosis.
2022-04-10 | GSE200385 | GEO
Project description:Aberrant NF-kB signaling fuels tumor growth in multiple human cancer types including both hematologic and solid malignancies. Chronic elevated alternative NF-kB signaling can be modeled in transgenic mice upon activation of a conditional NF-kB-inducing kinase (NIK) allele lacking the regulatory TRAF3 binding domain (NT3). Here, we report that expression of NT3 in the mesenchymal lineage with Osterix (Osx/Sp7)-Cre or Fibroblast Specific Protein (Fsp1)-Cre caused subcutaneous, soft tissue tumors. These tumors displayed significantly shorter latency and a greater multiple incidence rate in Fsp1-Cre;NT3 compared to Osx-Cre;NT3 mice, regardless of sex. Histological assessment revealed poorly differentiated solid tumors with some spindled patterns, as well as robust RelB (Relb) immunostaining, confirming activation of alternative NF-kB. Even though NT3 expression also occurs in the osteolineage in Osx-Cre;NT3 mice, we observed no bony lesions. The staining profiles and pattern of Cre expression in the two lines pointed to a mesenchymal tumor origin. Immunohistochemistry revealed that these tumors stain strongly for SMA (Acta2), although vimentin (Vim) staining was uniform only in Osx-Cre;NT3 tumors. Negative CD45 (Ptprc) and S100 immunostains precluded hematopoietic and melanocytic origins, respectively, while positive staining for CK19 (Krt19), typically associated with epithelia, was found in subpopulations of both tumors. Principal component, differential expression, and gene ontology analyses revealed that NT3 tumors are distinct from normal mesenchymal tissues and are enriched for NF-kB related biological processes. We conclude that constitutive activation of the alternative NF-kB pathway in the mesenchymal linage drives spontaneous sarcoma and provides a novel mouse model for NF-kB related sarcomas.
2020-09-25 | GSE158479 | GEO