Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA259198 | ENA |
REPOSITORIES: ENA
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Project description:Chromosome 5q deletions (del(5q)) are common in high-risk (HR) Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML); however, the gene regulatory networks that sustain these aggressive diseases are unknown. Reduced miR-146a expression in del(5q) HR-MDS/AML and miR-146a-/- hematopoietic stem/progenitor cells (HSPC) results in TRAF6/NF-κΒ activation. Increased survival and proliferation of HSPC from miR-146alow HR-MDS/AML is sustained by a neighboring haploid gene, SQSTM1 (p62), expressed from the intact 5q allele. Overexpression of p62 from the intact allele occurs through NF-κB-dependent feedforward signaling mediated by miR-146a deficiency. p62 is necessary for TRAF6-mediated NF-κB signaling, as disrupting the p62-TRAF6 signaling complex results in cell cycle arrest and apoptosis of MDS/AML cells. Thus, del(5q) HR-MDS/AML employs an intrachromosomal gene network involving loss of miR-146a and haploid overexpression of p62 via NF-κB to sustain TRAF6/NF-κB signaling for cell survival and proliferation. Interfering with the p62-TRAF6 signaling complex represents a therapeutic option in miR-146a-deficient and aggressive del(5q) MDS/AML.
2014-08-23 | GSE60649 | GEO
Project description:Chromosome 5q deletions (del(5q)) are common in high-risk (HR) Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML); however, the gene regulatory networks that sustain these aggressive diseases are unknown. Reduced miR-146a expression in del(5q) HR-MDS/AML and miR-146a-/- hematopoietic stem/progenitor cells (HSPC) results in TRAF6/NF-M-NM-:M-NM-^R activation. Increased survival and proliferation of HSPC from miR-146alow HR-MDS/AML is sustained by a neighboring haploid gene, SQSTM1 (p62), expressed from the intact 5q allele. Overexpression of p62 from the intact allele occurs through NF-M-NM-:B-dependent feedforward signaling mediated by miR-146a deficiency. p62 is necessary for TRAF6-mediated NF-M-NM-:B signaling, as disrupting the p62-TRAF6 signaling complex results in cell cycle arrest and apoptosis of MDS/AML cells. Thus, del(5q) HR-MDS/AML employs an intrachromosomal gene network involving loss of miR-146a and haploid overexpression of p62 via NF-M-NM-:B to sustain TRAF6/NF-M-NM-:B signaling for cell survival and proliferation. Interfering with the p62-TRAF6 signaling complex represents a therapeutic option in miR-146a-deficient and aggressive del(5q) MDS/AML. Four del(5q) MDS/AML patients with low miR-146a expression (5284, 8839, 8285, 4233) and 5 with high miR-146a expression (7957, 5534, 4688, 4982, 8412) were selected for microarray assay. RNA was reverse transcribed and labeled, and hybridized onto the GeneChip Human Gene 1.0 ST Array. A total of nine samples were included, and two groups are assigned based on miR-146a expression. Comparison comprises mRNA expression profile of low miR-146a group v.s. high miR-146a group.
2014-08-23 | E-GEOD-60649 | 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:NF-κB has an essential role in innate immune response and inflammation and is involved in cancer development and progression. We apply the SEC-PCP-SILAC method incorporating metabolic labeling, size exclusion chromatography and protein correlation profiling to construct a complex network of interactome rearrangement in response to NF-κB modulation in breast cancer cells. Our interaction network represents a complex insight into the dynamics of MCF-7 protein interactome associated with NF-κB pathway. Our dataset could serve as a basis for future studies characterizing role of NF-κB in breast cancer cellular pathways. This PRIDE project includes results from SILAC labeled and label-free replicates from the SEC-PCP-SILAC analysis of protein complexes in MCF-7 cells with inhibited and uninhibited NF-κB pathway, results from the immunoprecipitation experiment aimed at interaction partners of NF-κB factor RELA, analysis of total proteome after NF-κB inhibition, and results from SEC fractionation of untreated and unlabeled MCF-7 cells.
2024-02-28 | PXD040125 | Pride
Project description:This project aimed to identify a specific target for chromosome 8p deletions. Using large-scale functional-genomic screening data of over 527 well-characterized cancer cell lines. We were able to identify the dependency of SLC25A28 (Mitoferrin-2, MFRN2), a mitochondrial iron transporter, in chromosome 8p deleted cancer cell lines. Interestingly, we found that SLC25A37 (Mitoferrin-1, MFRN1), the paralog of MFRN2, resides on chromosome 8p and is frequently deleted in liver cancer. We found a strong correlation between the cellular dependency on MFRN2 and the MFRN1 expression levels, possibly explaining why MFRN2 is a synthetic lethal target for 8p deletions. Our study discovered MFRN2 as a target for a therapeutic strategy in chromosome 8p deleted cancer specimens. Further, it revealed MFRN1 as a biomarker that predicts the response to MFRN2-directed therapy.
2024-06-03 | PXD044780 | Pride
Project description:Aim： Use microarray analysis to understand the molecular mechanism underlying the effect of aristolochic acid (AA), a major active component of plants from the Aristolochiaceae family, in normal human kidney (HK-2) cells. Methods： HK-2 cells were treated with AA for 24 hours and cell viability was measured by a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide assay. Complementary DNA microarrays were used to investigate the gene expression pattern of HK-2 cells exposed to AA and the results of this study were in triplicate. Quantitative real-time RT-PCR assay was used to verify the microarray data for selected nuclear factor kappa B (NF-κB)-regulated genes. Furthermore, subcellular localization of NF-κB p65 was visualized by immunofluorescence confocal microscopy in HK-2 cells. NF-κB activity was examined by luciferase reporter assay in HK-2/NF-κB transgenic cells. Results： AA exhibited a dose-dependent cytotoxic effect in HK-2 cells and induced alterations in gene expression profiles related to DNA damage response, stress response, etc. In addition, 9 biological pathways associated with immunomodulatory functions were down-regulated in AA-treated HK-2 cells. Network analysis revealed that NF-κB played a central role in the network topology. Among NF-kB-regulated genes, 8 differentially expressed genes were verified by real-time RT-PCR. The inhibition of NF-κB activity by AA was further confirmed by immunofluorescence confocal microscopy and by NF-κB luciferase reporter assay. Conclusion： Our data revealed that AA could suppress NF-κB activity in normal human cells, perhaps partially accounting for the reported anti-inflammatory effects of some plants from the genus Aristolochia. HK-2 cells were grown in keratinocyte serum-free basal medium (Gibco) supplemented with 5 ng/ml of recombinant epidermal growth factor and 50 μg/ml of bovine pituitary extract without antibiotics in 5 % CO2 at 370C. HK-2 cells were seeded in 25-T flasks and incubated for 24 h before aristolochic acid treatment. Aristolochic acid (10 90 μM) were added to HK-2 cells for 24 h. The control cells received equal amounts of water only.
2010-09-24 | E-GEOD-18243 | biostudies-arrayexpress
Project description:Although therapy responsiveness to therapy in Burkitt lymphoma (BL) is high, relapsed disease and and chemoresistance remain a clinical challenge, and complete mechanisms underlying BL chemoresistance and how it can be circumvented is yet to be fully elucidated. In this study we present data showing that chymotrypsin-like serine proteases inhibitor Nα-tosyl-L-phenylalanine chloromethylketone (TPCK) and specific NF-κB inhibitor Bay-11 7082 can induce caspase-independent apoptosis in chemoresistant BL cells. We also demonstrate that both TPCK and Bay-11 7082-treatment leads to decreased NF-κB nuclear activity and that this is associated with sensitization of chemoresistant Burkitt lymphoma cells. Furthermore we investigated global transcriptional changes induced by Bay-11 7082 and TPCK in the DG-75 and Raji cell lines, respectively, by microarray analysis using Illumina BeadChips. TPCK-treatment of Raji and DG-75 cells resulted in 59 and 21 differently expressed genes, respectively, while Bay-11-treated Raji and DG-75 cells displayed 1403 and 8 differently expressed genes, respectively. Gene Ontology (GO) categorization confirmed enrichment of multiple GOs in Bay 11-treated Raji and DG-75 cells. Fifty percent of the 61 categories in Raji cells were categories sorting under Biological Processes and represented mostly increased gene expression. In DG-75 cells Bay-11 7082 induced significant gene ontology enrichment in only two categories, where the increased/decreased ratio was 1:1. Further unsupervised and supervised bioinformatics processing by Ingenuity Pathway Analysis indicated significant networks in response to TPCK and Bay 11 respectively, including association to NF-κB. Bay-11 7082 demonstrated deregulated NF-κB related members of receptor mediated cell death signaling, i.e TRAF2 and TRADD, as well as deregulated members of the NF-κB signaling pathway from the cytoplasmic compartment, i.e RELB, in Raji cells. Comparably NF-κB network analysis of Raji- and DG-75 cells treated with Bay-11 7082 and Raji cells treated with TPCK demonstrated deregulation of NF-κB target genes CD69 and IL8. These data indicates that NF-kB may play a role in overcoming chemoresistance in BL cells with defective classical apoptosis signaling. NF-κB network analysis of Raji- and DG-75 cells treated with Bay-11 7082 and Raji cells treated with TPCK
2014-01-19 | E-GEOD-31258 | biostudies-arrayexpress
Project description:Aneuploidy is prevalent in cancer, conferring fitness advantage, multidrug resistance, and poor prognosis. In contrast, experimentally induced aneuploidy often results in adverse effects and impaired proliferation. This paradox underscores the necessity of cancer cells to adapt to abnormal chromosome numbers. To identify molecular mechanisms of adaptation to aneuploidy, we initiated in vitro evolution of cells with extra chromosomes added via microcell-mediated chromosome transfer. To this end, we cultured cells in a nutrient-rich medium for 50 passages or plated the cells at a low density and selectively collected the largest colonies originating from a single cell (colony selection). One of the striking observations following evolution of cells with extra chromosome 5 in HCT116 cell line was the frequent loss of the 5q, while maintaining the 5p arm after in vitro evolution. Chromosome 5 is a frequent target of large copy number alterations in several malignancies, such as ovarian, gastric, and oesophageal cancer, and malignant myeloid diseases. Moreover, analysis of chromosome arm level events in the TCGA dataset clearly shows that loss of chromosome arm 5q and gain of 5p are among the most frequent events. We asked whether these specific changes in copy numbers of chromosome 5 – loss of 5q with simultaneous retention of 5p – could affect the proliferation of the evolved cells. To this end, we used the recently developed technique ReDACT-TR (Restoring Disomy in Aneuploid cells using CRISPR Targeting with Telomere Replacement (Girish et al., 2023)), and transfected cells of a separate clone of Htr5 (before evolution) with a gRNA that cuts near the centromere of chromosome 5, simultaneously with a cassette encoding ~100 repeats of the human telomere seed sequence. Targeting the q-arm generated two independent cell lines with 5p trisomy (Htr5p_1 and Htr5p_2), which were confirmed by FISH with probes specific for 5p and 5q arms and by shallow WGS. No cell lines with trisomy of the q-arm were generated, but we have obtained two diploid cell lines (Hdi5_1 and Hdi5_2), most likely due to the CRISPR/Cas9 induced loss of chromosome 5 (Papathanasiou, Markoulaki et al., 2021, Tsuchida, Brandes et al., 2023). The anaylsis of global proteomes of the ReDACT cell lines was then carried out using a TMT quantification strategy.
2025-01-14 | PXD056432 | Pride
Project description:Conventional type 1 dendritic cells (cDC1s) are critical for anti-tumor immunity. They acquire antigens from dying tumor cells and cross-present them to CD8+ T cells, promoting the expansion of tumor-specific cytotoxic T cells. However, the signaling pathways that govern the anti -tumor functions of cDC1s are poorly understood. We mapped the molecular pathways regulating intratumoral cDC1 maturation using single cell RNA sequencing. We identified NF κB and IFN pathways as being highly enriched in a subset of functionally mature cDC1s. The specific targeting of NF-κB or IFN pathways in cDC1s prevented the recruitment and activation of CD8+ T cells and the control of tumor growth. We identified an NF-κB-dependent IFN-γ-regulated gene network in cDC1s, including cytokines and chemokines specialized in the recruitment and activation of cytotoxic T cells. We used single cell transcriptomes to map the trajectory of intra-tumoral cDC1 maturation which revealed the dynamic reprogramming of tumor-infiltrating cDC1s by NF-κB and IFN signaling pathways. This maturation process was perturbed by specific inactivation of either NF-κB or IRF1 in cDC1s, resulting in impaired expression of IFN-γ-responsive genes and consequently a failure to efficiently recruit and activate anti-tumoral CD8+ T cells. Finally, we demonstrate the relevance of these findings to cancer patients, showing that activation of the NF-κB/IRF1 axis in association with cDC1s is linked with improved clinical outcome. The NF-κB/IRF1 axis in cDC1s may therefore represent an important focal point for the development new diagnostic and therapeutic approaches to improve cancer immunotherapy.
2021-08-16 | GSE171870 | GEO