FYN-TRAF3IP2 induces NF-κB signaling-driven peripheral T cell lymphoma.
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ABSTRACT:
SUBMITTER: Moon CS
PROVIDER: S-EPMC8081346 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:FYN-TRAF3IP2 expression in hematopoietic progenitors induces T cell transformation in mice and cooperates with loss of the Tet2 tumor suppressor in PTCL development. To investigate the oncogenic activity of FYN-TRAF3IP2, we analyzed the lymphomagenic effects of expressing this gene fusion alone and in cooperation with loss of the Tet2 tumor suppressor gene in vivo. In these experiments, we first infected hematopoietic progenitors from CD4-specific tamoxifen-inducible Cre Tet2 conditional knockout mice (CD4 Cre-ERT2, Tet2fl/fl) with bicistronic retroviruses expressing wild type TRAF3IP2 and GFP, FYN-TRAF3IP2 and GFP, or GFP alone and injected these intravenously into isogenic recipients. Transplanted mice were then treated with vehicle only, to test the oncogenic effects of TRAF3IP2, FYN-TRAF3IP2 or GFP expression; or with tamoxifen, to evaluate the effects of TRAF3IP2, FYN-TRAF3IP2 or GFP expression in concert with genetic loss of Tet2 in CD4 T cells. In this setting, all animals transplanted with GFP-expressing progenitors remained lymphoma free at the end of follow up and one animal transplanted with wild type TRAF3IP2 GFP expressing cells developed a CD8+ T cell lymphoma. In contrast, 4/10 (40%) vehicle treated mice transplanted with FYN-TRAF3IP2-expressing cells and 5/10 (50%) tamoxifen treated mice transplanted with FYN-TRAF3IP2-expressing cells developed clonal CD4-restricted mature T cell lymphomas. To further analyze the lymphomagenic effect of the fusion gene, we performed transcriptomic profiling of FYN-TRAF3IP2-induced mouse CD4+ GFP+ PTCL tumor lymphocytes compared with normal mouse CD4+ T cells by RNAseq.
2020-10-01 | GSE138416 | GEO
Project description:Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Up to 30% of PTCL lack distinctive features and are classified as PTCL, not otherwise specified (PTCL-NOS). To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we perform RNA-sequencing of 18 cases and validate results in an independent cohort of 37 PTCL cases. We identify FYN-TRAF3IP2, KHDRBS1-LCK and SIN3A-FOXO1 as new in-frame fusion transcripts, with FYN-TRAF3IP2 as a recurrent fusion detected in 8 of 55 cases. Using ex vivo and in vivo experiments, we demonstrate that FYN-TRAF3IP2 and KHDRBS1-LCK activate signaling pathways downstream of the T cell receptor (TCR) complex and confer therapeutic vulnerability to clinically available drugs.
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Project description:FYN-TRAF3IP2 activating fusion oncogene in peripheral T-cell lymphoma
| PRJNA575793 | ENA
Project description:Medial vascular calcification, associated with enhanced mortality in chronic kidney disease (CKD), is fostered by osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Here, we describe that serum- and glucocorticoid-inducible kinase 1 (SGK1) was upregulated in VSMCs under calcifying conditions. In primary human aortic VSMCs, overexpression of constitutively active SGK1S422D, but not inactive SGK1K127N, upregulated osteo-/chondrogenic marker expression and activity, effects pointing to increased osteo-/chondrogenic transdifferentiation. SGK1S422D induced nuclear translocation and increased transcriptional activity of NF-κB. Silencing or pharmacological inhibition of IKK abrogated the osteoinductive effects of SGK1S422D. Genetic deficiency, silencing, and pharmacological inhibition of SGK1 dissipated phosphate-induced calcification and osteo-/chondrogenic transdifferentiation of VSMCs. Aortic calcification, stiffness, and osteo-/chondrogenic transdifferentiation in mice following cholecalciferol overload were strongly reduced by genetic knockout or pharmacological inhibition of Sgk1 by EMD638683. Similarly, Sgk1 deficiency blunted vascular calcification in apolipoprotein E-deficient mice after subtotal nephrectomy. Treatment of human aortic smooth muscle cells with serum from uremic patients induced osteo-/chondrogenic transdifferentiation, effects ameliorated by EMD638683. These observations identified SGK1 as a key regulator of vascular calcification. SGK1 promoted vascular calcification, at least partly, via NF-κB activation. Inhibition of SGK1 may, thus, reduce the burden of vascular calcification in CKD.
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Project description:IntroductionImproving treatments for Diffuse Large B-Cell Lymphoma (DLBCL) is challenged by the vast heterogeneity of the disease. Nuclear factor-κB (NF-κB) is frequently aberrantly activated in DLBCL. Transcriptionally active NF-κB is a dimer containing either RelA, RelB or cRel, but the variability in the composition of NF-κB between and within DLBCL cell populations is not known.ResultsHere we describe a new flow cytometry-based analysis technique termed "NF-κB fingerprinting" and demonstrate its applicability to DLBCL cell lines, DLBCL core-needle biopsy samples, and healthy donor blood samples. We find each of these cell populations has a unique NF-κB fingerprint and that widely used cell-of-origin classifications are inadequate to capture NF-κB heterogeneity in DLBCL. Computational modeling predicts that RelA is a key determinant of response to microenvironmental stimuli, and we experimentally identify substantial variability in RelA between and within ABC-DLBCL cell lines. We find that when we incorporate NF-κB fingerprints and mutational information into computational models we can predict how heterogeneous DLBCL cell populations respond to microenvironmental stimuli, and we validate these predictions experimentally.DiscussionOur results show that the composition of NF-κB is highly heterogeneous in DLBCL and predictive of how DLBCL cells will respond to microenvironmental stimuli. We find that commonly occurring mutations in the NF-κB signaling pathway reduce DLBCL's response to microenvironmental stimuli. NF-κB fingerprinting is a widely applicable analysis technique to quantify NF-κB heterogeneity in B cell malignancies that reveals functionally significant differences in NF-κB composition within and between cell populations.
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Project description:BackgroundDHX15 is one of the RNA helicase family members involving in several biological processes. Studies have reported that overexpression of DHX15 is related to cancer progression. However, the role of DHX15 in Burkitt lymphoma (BL) and latent Epstein-Barr virus (EBV) infection remains to be elucidated.MethodsExpression of DHX15 was measured in BL patient by immunohistochemical staining. In vitro study, a CCK-8 assay was used to analyze cell proliferation and flow cytometry was performed to assess cell cycle, apoptosis and mitochondria membrane potential. Members of NF-κB signaling pathway and apoptotic-related proteins expression were measured by western-blot. EBV latent infection products and RNA polymerase III transcripts expression were determined by quantitative real-time PCR and western-blot. In vivo study, HE, IHC, TUNEL and ISH assays were used to analyze the effect of DHX15 on subcutaneous tumor nodes formation.ResultsDHX15 was overexpressed in Burkitt lymphoma patients and tends to be associated with poor progression-free survival and poor overall survival. Knockdown of DHX15 significantly inhibited BL tumor growth, reduced cell proliferation, induced cell cycle arrest and increased cell apoptosis. Further analysis showed that canonical NF-κB signaling and its downstream targets, mitochondria and Caspase were involved in the increased cell apoptosis after DHX15 gene knockdown. Furthermore, knockdown of DHX15 reduced EBV latent infection products expression and inhibited RNA polymerase III activity.ConclusionDHX15 may be an oncogene in the development of BL and a potential therapeutic target for the treatment of BL and latent EBV infection.
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Project description:To interrogate signaling pathways activated in mantle cell lymphoma (MCL) in vivo, we contrasted gene expression profiles of 55 tumor samples isolated from blood and lymph nodes from 43 previously untreated patients with active disease. In addition to lymph nodes, MCL often involves blood, bone marrow, and spleen and is incurable for most patients. Recently, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib demonstrated important clinical activity in MCL. However, the role of specific signaling pathways in the lymphomagenesis of MCL and the biologic basis for ibrutinib sensitivity of these tumors are unknown. Here, we demonstrate activation of B-cell receptor (BCR) and canonical NF-κB signaling specifically in MCL cells in the lymph node. Quantification of BCR signaling strength, reflected in the expression of BCR regulated genes, identified a subset of patients with inferior survival after cytotoxic therapy. Tumor proliferation was highest in the lymph node and correlated with the degree of BCR activation. A subset of leukemic tumors showed active BCR and NF-κB signaling apparently independent of microenvironmental support. In one of these samples, we identified a novel somatic mutation in RELA (E39Q). This sample was resistant to ibrutinib-mediated inhibition of NF-κB and apoptosis. In addition, we identified germ line variants in genes encoding regulators of the BCR and NF-κB pathway previously implicated in lymphomagenesis. In conclusion, BCR signaling, activated in the lymph node microenvironment in vivo, appears to promote tumor proliferation and survival and may explain the sensitivity of this lymphoma to BTK inhibitors.
| S-EPMC4937360 | biostudies-literature
Project description:Oxidative stress in the lumbar disc leads to the degeneration of nucleus pulposus (NP). However, the molecular mechanisms underlying this process remain unclear. In this study, we delineated a key calcium-binding protein, S100A9, which was induced by oxidative stress and was highly expressed in the degenerative NP. Immunofluorescence staining and Western blotting revealed that S100A9 induced NP cell apoptosis in vitro by up-regulating the expression of pro-apoptotic markers, including cleaved caspase-3, cytochrome c and Bax. Moreover, RT-PCR analyses revealed that the expression of S100A9 caused NP matrix degradation by up-regulating the expression of matrix degradation enzymes and increased the inflammatory response by up-regulating cytokine expression. Therefore, S100A9 induced NP cell degeneration by exerting pro-apoptotic, pro-degradation and pro-inflammatory effects. The detailed mechanism underlying S100A9-induced NP degeneration was explored by administering SC75741, a specific NF-κB inhibitor in vitro. We concluded that S100A9 induced NP cell apoptosis, caused matrix degradation and amplified the inflammatory response through the activation of the NF-κB signalling pathway. Inhibition of these pro-apoptotic, pro-degradation and pro-inflammatory effects induced by S100A9 in NP may be a favourable therapeutic strategy to slow lumbar disc degeneration.
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Project description:BackgroundThe B-cell lymphoma 6 (BCL6) oncogene is required for the survival of diffuse large B-cell lymphoma (DLBCL), which is incurable using conventional chemotherapy. Thus, it is imperative to improve the survival of patients with DLBCL. Disulfide (DSF) has been shown to have anticancer effects, but its effect on DLBCL remains unclear.MethodsFour DLBCL cell lines (OCI-LY1, OCI-LY7, OCI-LY10 and U2932) and primary DLBCL cells from eight newly diagnosed DLBCL patients were pretreated with DSF alone or in combination with Cu. Cell morphology was observed under microscope. Flow cytometry was performed to evaluate the cell apoptosis, cell cycle, the mitochondrial membrane potential and the intracellular accumulation of reactive oxygen species (ROS). The protein expression was respectively measured by flow cytometry and western blotting.ResultsDSF or DSF/Cu exhibited a marked inhibitory effect on the growth of DLBCL cells, accompanied by cell cycle arrest at the G0/G1 phase. Meanwhile, DSF or DSF/Cu significantly induced DLBCL cells apoptosis. Further study revealed that DSF or DSF/Cu promoted apoptosis by inhibiting NF-κB signaling pathway. Interestingly, DSF/Cu significantly reduced BCL6 and AIP levels. In addition, DSF significantly up-regulate p53 protein in OCI-LY7 and OCI-LY10 while down-regulate p53 protein in OCI-LY1 and U2932.ConclusionThese results provided evidence for the anti-lymphoma effects of DSF on DLBCL and suggested that DSF has therapeutic potential to DLBCL.
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Project description:The NF-κB essential modulator NEMO is the core regulatory component of the inhibitor of κB kinase complex, which is a critical checkpoint in canonical NF-κB signaling downstream of innate and adaptive immune receptors. In response to various stimuli, such as TNF or IL-1β, NEMO binds to linear or M1-linked ubiquitin chains generated by LUBAC, promoting its oligomerization and subsequent activation of the associated kinases. Here we show that M1-ubiquitin chains induce phase separation of NEMO and the formation of NEMO assemblies in cells after exposure to IL-1β. Phase separation is promoted by both binding of NEMO to linear ubiquitin chains and covalent linkage of M1-ubiquitin to NEMO and is essential but not sufficient for its phase separation. Supporting the functional relevance of NEMO phase separation in signaling, a pathogenic NEMO mutant, which is impaired in both binding and linkage to linear ubiquitin chains, does not undergo phase separation and is defective in mediating IL-1β-induced NF-κB activation.
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