Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA354537 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Deregulated expression of HDAC9 in B cells promotes development of lymphoproliferative disease and lymphoma in mice [HDAC9 transgenic]
| PRJNA354538 | ENA
Project description:Deregulated expression of HDAC9 in B cells promotes development of lymphoproliferative disease and lymphoma in mice
| PRJNA354311 | ENA
Project description:Histone deacetylase 9 (HDAC9) is expressed in B cells, and its overexpression has been observed in B-lymphoproliferative disorders, including B-cell non-Hodgkin lymphoma (B-NHL). We examined HDAC9 protein expression and copy number alterations in primary B-NHL samples, identifying high HDAC9 expression among various lymphoma entities and HDAC9 copy number gains in 50% of diffuse large B-cell lymphoma (DLBCL). To study the role of HDAC9 in lymphomagenesis, we generated a genetically engineered mouse (GEM) model that constitutively expressed an HDAC9 transgene throughout B-cell development under the control of the immunoglobulin heavy chain (IgH) enhancer (Eμ). Here, we report that the Eμ-HDAC9 GEM model develops splenic marginal zone lymphoma and lymphoproliferative disease (LPD) with progression towards aggressive DLBCL, with gene expression profiling supporting a germinal center cell origin, as is also seen in human B-NHL tumors. Analysis of Eμ-HDAC9 tumors suggested that HDAC9 might contribute to lymphomagenesis by altering pathways involved in growth and survival, as well as modulating BCL6 activity and p53 tumor suppressor function. Epigenetic modifications play an important role in the germinal center response, and deregulation of the B-cell epigenome as a consequence of mutations and other genomic aberrations are being increasingly recognized as important steps in the pathogenesis of a variety of B-cell lymphomas. A thorough mechanistic understanding of these alterations will inform the use of targeted therapies for these malignancies. These findings strongly suggest a role for HDAC9 in B-NHL and establish a novel GEM model for the study of lymphomagenesis and, potentially, preclinical testing of therapeutic approaches based on histone deacetylase inhibitors.
2016-11-17 | GSE89955 | GEO
Project description:Histone deacetylase 9 (HDAC9) is expressed in B cells, and its overexpression has been observed in B-lymphoproliferative disorders, including B-cell non-Hodgkin lymphoma (B-NHL). We examined HDAC9 protein expression and copy number alterations in primary B-NHL samples, identifying high HDAC9 expression among various lymphoma entities and HDAC9 copy number gains in 50% of diffuse large B-cell lymphoma (DLBCL). To study the role of HDAC9 in lymphomagenesis, we generated a genetically engineered mouse (GEM) model that constitutively expressed an HDAC9 transgene throughout B-cell development under the control of the immunoglobulin heavy chain (IgH) enhancer (Eμ). Here, we report that the Eμ-HDAC9 GEM model develops splenic marginal zone lymphoma and lymphoproliferative disease (LPD) with progression towards aggressive DLBCL, with gene expression profiling supporting a germinal center cell origin, as is also seen in human B-NHL tumors. Analysis of Eμ-HDAC9 tumors suggested that HDAC9 might contribute to lymphomagenesis by altering pathways involved in growth and survival, as well as modulating BCL6 activity and p53 tumor suppressor function. Epigenetic modifications play an important role in the germinal center response, and deregulation of the B-cell epigenome as a consequence of mutations and other genomic aberrations are being increasingly recognized as important steps in the pathogenesis of a variety of B-cell lymphomas. A thorough mechanistic understanding of these alterations will inform the use of targeted therapies for these malignancies. These findings strongly suggest a role for HDAC9 in B-NHL and establish a novel GEM model for the study of lymphomagenesis and, potentially, preclinical testing of therapeutic approaches based on histone deacetylase inhibitors.
2016-11-17 | GSE89954 | GEO
Project description:Aberrant expression of the proto-oncogene BCL6 is a driver of tumorigenesis in diffuse large B cell lymphoma (DLBCL). Mice overexpressing BCL6 from the B cell-specific immunoglobulin heavy chain μ intron promoter (Iμ-Bcl6 Tg/+ ) develop B cell lymphomas with features typical of human DLBCL. B cell lymphoma development in these mice is tightly controlled by T cells; however, the mechanisms of this immune surveillance are poorly understood. Here we show that CD4 T cells contribute to the control of lymphoproliferative disease in lymphoma-prone Iμ-Bcl6 Tg/+ mice. Furthermore, we reveal that this CD4 T-cell immuno-surveillance requires signaling by the co-stimulatory molecule, CD137 ligand (CD137L; also known as 4-1BBL), which promotes the transition of pre malignant B cells with an activated phenotype into the germinal center stage, preventing their hazardous accumulation. Thus, CD137L-mediated CD4 T cell immuno-surveillance adds another layer of protection against B-cell malignancy to that provided by CD8 T-cell cytotoxicity.
2023-01-04 | GSE196100 | GEO
Project description:Muscle denervation due to injury, disease or aging results in impaired motor function. Restoring neuromuscular communication requires axonal regrowth and regeneration of neuromuscular synapses. Muscle activity inhibits neuromuscular synapse regeneration. The mechanism by which muscle activity regulates regeneration of synapses is poorly understood. Dach2 and Hdac9 are activity-regulated transcriptional co-repressors that are highly expressed in innervated muscle and suppressed following muscle denervation. Here, we report that Dach2 and Hdac9 inhibit regeneration of neuromuscular synapses. Importantly, we identified Myog and Gdf5 as muscle-specific Dach2/Hdac9-regulated genes that stimulate neuromuscular regeneration in denervated muscle. Interestingly, Gdf5 also stimulates presynaptic differentiation and inhibits branching of regenerating neurons. Finally, we found that Dach2 and Hdac9 suppress miR206 expression, a microRNA involved in enhancing neuromuscular regeneration. RNAseq on innervated and 3 day denervated adult soleus muscle from wildtype mice is compared with that from 3 day denervated soleus muscle from Dach2/Hdac9 deleted mice to identify Dach2/Hdac9-regulated genes.
2015-10-29 | E-GEOD-58669 | biostudies-arrayexpress
Project description:BTG1 is recurrently mutated in the MCD/C5 subgroup of diffuse large B cell lymphoma (DLBCL), but the functions of this gene in lymphomagenesis have never been investigated so far. Here we provide evidence that Btg1 knock out accelerates the development of a lethal lymphoproliferative disease driven by Bcl2 overexpression. Exploring the clinical association between BTG1 mutation and extranodal dissemination, we discovered BCAR1 as a new BTG1 partner. Following BTG1 inactivation, overactivation of the BCAR1-RAC1 pathway induced major remodeling of the actin cytoskeleton and increased migration capacities of lymphoma cells in vitro and in vivo. These modifications were targetable with the SRC inhibitor dasatinib, which opens interesting clinical perspectives in BTG1 mutated DLBCL
2022-03-10 | MSV000089045 | MassIVE
Project description:Proper regulation of nuclear factor κB (NF-κB) transcriptional activity is required for normal lymphocyte function, and deregulated NF-κB signaling can facilitate lymphomagenesis. We demonstrate that the API2-MALT1 fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-κB–inducing kinase (NIK) at arginine 325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-κB signaling, enhanced B cell adhesion, and apoptosis resistance. Our study reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical NF-κB pathway in B lymphoproliferative disease.
2011-01-30 | GSE25527 | GEO
Project description:Purpose: Marek's disease virus (MDV) is an oncogenic herpesvirus that can induce T-cell lymphoma. Long noncoding RNA (lncRNA) strongly associated with various cancers and many other diseases. In chickens, lncRNAs have not been comprehensively identified. Here, we profiled mRNA and lncRNA repertoires in three groups of spleens from MDV-infected and non-infected chickens, including seven tumorous spleens (TS) from MDV-infected chickens, five spleens from the survivors (SS) without any lesion after MDV infection, and five noninfected spleens (NS) from chickens, to explore the underlying mechanism of host resistance to Marek's disease (MD). Results: By using precise lncRNA identification pipeline, we identified 1315 putative lncRNAs and 1166 known lncRNAs in spleen tissue. Genomic features of putative lncRNAs were characterized. Differentially expressed mRNAs, putative lncRNAs and known lncRNAs were profiled. Some previously reported MD resistance candidate genes, such as CTLA4, HDAC9 and CD72, were also found in our differentially expressed genes list. Moreover, we found that several intergroup specifically deregulated genes were involved in important biological processes and pathways, including B cell activation and Wnt signaling pathway. We conducted co-expression network using WGCNA and identified several hub genes that may play pivotal roles in MD resistance and tumorigenesis, e.g. CTLA4, SWAP70, CXCL12 and JCHAIN. According to the expression relationship between lncRNAs and MD resistance candidate mRNAs, five deregulated lncRNAs may implicate the chicken immunity by directly or indirectly regulating those hub genes. Conclusions: We profiled both lncRNA and mRNA expression patterns in MDV-infected chicken spleens. Expression variations of intergroup specifically deregulated genes engaged in important immune process likely contributed to robust immune system in the survivors. Some oncogenesis or MD resistance related genes deregulated between groups, like CTLA4, HDAC9 and CD72 were found. Co-expression network analysis manifested that lncRNAs may affect MD resistance and tumorigenesis in chicken spleens through their impact on expression of CTLA4, SWAP70 and some other genes that are critical in many important biological processes, such as B lymphocyte proliferation and activation.
2019-02-18 | GSE124133 | GEO
Project description:Patients with heterozygous missense mutations in the ACTA2 or MYH11 genes are known to exhibit thoracic aortic aneurysm (TAA) and a risk of early onset aortic dissection. However, less common phenotypes involving arterial obstruction are also observed, including coronary and cerebrovascular stenotic disease. Recently an epigenetic complex containing the histone deacetylase HDAC9 and the long noncoding RNA, MALAT1 was implicated in pathologic vascular smooth muscle cell phenotypic changes in aneurysmal disease, however its involvement in stenotic disease has not been explored. Herein we implicate the HDAC9-MALAT1 complex in transcriptional silencing of contractile associated gene products, known to undergo downregulation in stenotic lesions. Furthermore, neointimal formation was inhibited in Hdac9 or Malat1 deficient mice with preservation of contractile protein expression. Pharmacologic targeting of the complex through either MALAT1 antisense oligonucleotides or inhibition of the methyltransferase EZH2 reduced neointimal formation. In conclusion, we report the implication of the HDAC9-MALAT1 complex in stenotic disease and demonstrate that pharmacologic therapy based on epigenetic targets can ameliorate arterial obstruction in an experimental system.
2021-09-01 | GSE120394 | GEO