Mus musculus
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PROVIDER: PRJNA354538 | ENA |
REPOSITORIES: ENA
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Project description:Deregulated expression of HDAC9 in B cells promotes development of lymphoproliferative disease and lymphoma in mice [Bcell subsets]
| PRJNA354537 | 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:Epstein-Barr virus (EBV) is a major cause of immunosuppression-related lymphomas. EB-driven lymphoproliferative disease complicates up to 20% of transplants, and EBV is a major cause of human immunodeficieciency virus associated lymphomas. Despite successful antiretroviral therapy, the incidence of EBV-associated Hodgkin lymphoma continues to increase in HIV+ individuals. To gain insights into EBV membrane oncoprotein effects on B-cell growth, survival and pathogenesis in vivo, we generated transgenic mouse models, in which knock-in mice transgenically express control GFP or EBV latent membrane proteins (LMP) 1 and 2A under the control of the AICDA promoter. Upon T and NK-cell depletion by antibody cocktail, LMP1 and 2A co-expression drove explosive growth of plasmablastic lymphoma-like cells, which proliferated in the spleen, caused severe end-organ damage and death. RNAseq profiling identified genome-wide LMP1 and 2A effects on B-cell gene expression, including dramatic effects on chemokine and cytokine production. While cells exhibited plasmablast features, LMP1 and 2A co-expression also induced mixed hematopoietic lineage markers, a well described but incompletely understood feature of Hodgkin lymphoma. Collectively, our results identify synergistic effects of EBV membrane oncoprotein expression, and highlight their role in lymphoproliferative diseases of immunocompromised hosts.
2017-03-16 | GSE93827 | GEO
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:Attempts at modeling chromosomal translocations involving MALT1 gene, hallmarks of human mucosa-associated lymphoid tissue (MALT) lymphoma, have failed to reproduce the disease in mice. Here we describe a transgenic model in which MALT1 expression was targeted to mouse hematopoietic stem/progenitor cells. In Sca1-MALT1 mice, MALT1 deregulation activated the NF-kappaB pathway in Sca1+ cells, promoting selective B-cell differentiation and mature lymphocyte accumulation in extranodal tissues, progressively leading to the development of clonal B-cell lymphomas. These tumors recapitulated the histopathological features of human MALT lymphomas, presenting typical lymphoepithelial lesions and plasmacytic differentiation. Transcriptional profiling of Sca1-MALT1 murine lymphomas revealed overlapping molecular signatures with human MALT lymphomas, including MALT1-mediated NFkappaB activation, pro-inflammatory signaling and XBP1-induced plasmacytic differentiation. Moreover, murine Malt1 showed proteolytic activity by cleaving Bcl10 in Sca1-MALT1 lymphomas. Our novel technological approach has allowed modeling human MALT lymphoma in mice, which represent unique tools study MALT lymphoma biology and evaluate anti-MALT1 therapies. Keywords: Genetic modification, wt vs. transgenic, disease analysis, MALT lymphoma 9 samples were analized of which 5 were splenic lymphomas from Sca1-MALT1 transgenic mice and 4 were spleens from WT mice.
2012-07-09 | E-GEOD-25637 | biostudies-arrayexpress
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