Transcriptional state of T-cells from Atm-proficient and Atm-deficient mice in response to B-cell lymphoma
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE136773 | GEO | 2019/09/04
REPOSITORIES: GEO
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Project description:Transcriptional state of T-cells from Atm-proficient and Atm-deficient mice in response to B-cell lymphoma
| PRJNA563628 | ENA
Project description:To find genes deregulated in the pathogenisis of T-cells in Atm deficient mice, we performed expression profiling of Atm deficient thymic lymphomas, wildtype thymi and Atm deficient thymi without macroscopic enlargement, representing an intermediate stage in the process of tumorigenisis. Keywords: genetic modification, disease state analysis
2008-07-15 | GSE10807 | GEO
Project description:genomic profiling of murine thymocytes of Atm deficient mice with and without T-cell lymphoma Keywords: genetic modification
2008-07-15 | GSE10844 | GEO
Project description:Ataxia-telangiectasia mutated (ATM) kinase plays a central role in maintaining genomic integrity. In both humans and mice, ATM deficiency is associated with an increased incidence of lymphoid cancers that are primarily T cell in origin. We demonstrate here that when T cells are removed as targets for lymphomagenesis and as mediators of immune surveillance, ATM-deficient mice exclusively develop early onset IgM+ B cell lymphomas that by histology and gene expression profiling resemble the activated B cell-like (ABC) subset of human diffuse large B cell lymphomas (DLBCL). These ATM-deficient B cell tumors show considerable chromosomal instability and a recurrent genomic amplification of a 4.48 Mb region on chromosome 18 that contains Malt1 and is orthologous to a region similarly amplified in human ABC-DLBCL. Further, the amplification of Malt1 in these lymphomas correlates with their dependence on NF-kB, MALT1, and BCR signaling for survival, paralleling human ABC-DLBCL. This study reveals that ATM protects against development of B cell lymphomas that model human ABC-DLBCL and identifies a role for T cells in preventing the emergence of these tumors. We performed gene expression profiling on nine ATMKO.CD3epsilonKO lymphoma cell lines (n=12, 3 technical repeats). We analyzed gene expression of anti-IgM stimulated primary B cells from both ATMKO.CD3epsilonKO (n=7, 5 technical repeats) and ATMWT.CD3epsilonKO mice (n=2), and GC B cells isolated from SRBC-immunized ATMWT mice (n=3, 1 biological repeat and 2 technical repeats). We analyzed gene expression following treatment of two ATMKO.CD3epsilonKO lymphoma cell lines with the BTK inhibitor, PCI-32765, at time points (1, 3, 6, and 24 hours) as compared to time points with vehicle (DMSO) (n=8).
2015-12-09 | E-GEOD-68505 | biostudies-arrayexpress
Project description:Ataxia-telangiectasia mutated (ATM) kinase plays a central role in maintaining genomic integrity. In both humans and mice, ATM deficiency is associated with an increased incidence of lymphoid cancers that are primarily T cell in origin. We demonstrate here that when T cells are removed as targets for lymphomagenesis and as mediators of immune surveillance, ATM-deficient mice exclusively develop early onset IgM+ B cell lymphomas that by histology and gene expression profiling resemble the activated B cell-like (ABC) subset of human diffuse large B cell lymphomas (DLBCL). These ATM-deficient B cell tumors show considerable chromosomal instability and a recurrent genomic amplification of a 4.48 Mb region on chromosome 18 that contains Malt1 and is orthologous to a region similarly amplified in human ABC-DLBCL. Further, the amplification of Malt1 in these lymphomas correlates with their dependence on NF-kB, MALT1, and BCR signaling for survival, paralleling human ABC-DLBCL. This study reveals that ATM protects against development of B cell lymphomas that model human ABC-DLBCL and identifies a role for T cells in preventing the emergence of these tumors.
2015-12-09 | GSE68505 | GEO
Project description:Highly rearranged and mutated cancer genomes present major challenges in the identification of pathogenetic events driving the cancer process. Here, we engineered lymphoma-prone mice with chromosomal instability to assess the utility of mouse models in cancer gene discovery and the extent of cross-species overlap in cancer-associated copy number aberrations. Integrating with targeted re-sequencing, our comparative oncogenomic studies efficiently identified FBXW7 and PTEN as commonly deleted or mutated tumor suppressors in human T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). More generally, the murine cancers acquire widespread recurrent clonal amplifications and deletions targeting loci syntenic to alterations present in not only human T-ALL but also diverse tumors of hematopoietic, mesenchymal and epithelial types. These results thus support the view that murine and human tumors experience common biological processes driven by orthologous genetic events as they evolve towards a malignant phenotype. The highly concordant nature of genomic events encourages the use of genome unstable murine cancer models in the discovery of biologically relevant driver events in human cancer. Experiment Overall Design: 18 lymphoma samples from Atm-/-, mTerc-/-, p53-/- triple knock-out mice were analyzed. 3 week old hymus RNA from healthy mice of p53 Hets was used as reference. Each sample was hybridized with dye-swap replica.
2008-06-15 | E-GEOD-7607 | biostudies-arrayexpress
Project description:Deficiencies in the ATM gene are the underlying cause for ataxia telangiectasia, a congenital syndrome characterized by neurological, motor and immunological defects, as well as a predisposition to cancer risks. MicroRNAs (miRNAs) are small regulators of post-transcriptional gene expression and a useful tool for cancer diagnosis, staging, and prediction of therapeutic responses to clinical regimens. In particular, miRNAs have been used to develop signatures for breast cancer profiling. We are interested in the consequences of ATM deficiency on miRNA expression in breast epithelial cells and the potential contribution to cancer predisposition. In this study we investigate the effects of ATM loss on the miRNA expression and related gene expression changes in normal human mammary epithelial cells (HME-CC). We have identified 81 significantly differently expressed miRNAs in the ATM-deficient HME-CCs using small RNA sequencing. Many of these differentially expressed miRNAs have been described and implicated in tumorigenesis and proliferation. These changes include down-regulation of tumor suppressor miRNAs, such as hsa-miR-29c and hsa-miR-16, as well as the over-expression of pro-oncogenic miRNAs hsa-miR-93 and hsa-mir-221. All 81 miRNAs were combined with genome wide gene expression profiles to investigate possible targets of miRNA regulation. We identified messenger RNA (mRNA) targets of these miRNAs that were also significantly regulated after the depletion of ATM. Predicted targets included many genes implicated in cancer formation and progression, including SOCS1 and the proto-oncogene MAF. Integrated analysis of miRNA and mRNA expression allows us to build a more complete understanding of the pathways and networks involved in the breast cancer predisposition observed in individuals deficient in ATM. This study highlights miRNA and predicted mRNA target expression changes in ATM-deficient HME-CCs and suggests a mechanism for the breast cancer-prone phenotype seen in ATM deficient cells and patients. Additionally, this study provides preliminary data for defining miRNA profiles that may be used prognostic biomarkers for breast cancer predisposition. Examination of small RNA population in human mammary epithelial cell lines. Each condition was preformed in triplicate. This submission represents the transcriptome component of study.
2013-08-22 | E-GEOD-36082 | biostudies-arrayexpress
Project description:Highly rearranged and mutated cancer genomes present major challenges in the identification of pathogenetic events driving the cancer process. Here, we engineered lymphoma-prone mice with chromosomal instability to assess the utility of mouse models in cancer gene discovery and the extent of cross-species overlap in cancer-associated copy number aberrations. Integrating with targeted re-sequencing, our comparative oncogenomic studies efficiently identified FBXW7 and PTEN as commonly deleted or mutated tumor suppressors in human T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). More generally, the murine cancers acquire widespread recurrent clonal amplifications and deletions targeting loci syntenic to alterations present in not only human T-ALL but also diverse tumors of hematopoietic, mesenchymal and epithelial types. These results thus support the view that murine and human tumors experience common biological processes driven by orthologous genetic events as they evolve towards a malignant phenotype. The highly concordant nature of genomic events encourages the use of genome unstable murine cancer models in the discovery of biologically relevant driver events in human cancer. Experiment Overall Design: 22 lymphoma samples from Atm-/-, mTerc-/-, p53-/- triple knock-out mice were analyzed. DNA from healthy mice of the same line was used as reference. Each sample was hybridized with dye-swap replica.
2008-06-15 | E-GEOD-7600 | biostudies-arrayexpress
Project description:The expression of interferon-related genes was more enhanced in irradiated ATM-deficient mouse embryonic fibroblasts (MEFs) than in irradiated ATM wild-type MEFs. Nonirradiated-ATM-WT vs Irradiated-ATM-WT vs Nonirradaited-ATM-KO vs IrradiatedATM-KO
2012-06-19 | E-GEOD-23116 | biostudies-arrayexpress
Project description:In cerebellar atrophy of 12-month-old ATM-null mice, transcriptome upregulations concern most neurotransmission and neuropeptide pathways, while downregulations affect prominently Itpr1, Usp2 and non-coding RNA In cerebellar atrophy of 12-month-old ATM-null mice, transcriptome upregulations concern most neurotransmission and neuropeptide pathways, while downregulations affect prominently Itpr1, Usp2 and non-coding RNA The autosomal recessive disorder Ataxia-Telangiectasia is caused by dysfunction of stress response protein ATM. In the nucleus of proliferating cells, ATM senses DNA double-strand breaks and coordinates their repair. This role explains T-cell dysfunction and tumor risk. However, it remains unclear whether this function is relevant for postmitotic neurons and underlies the cerebellar atrophy, since ATM is cytoplasmic in postmitotic neurons. Here, we used ATM-null mice that survived early immune deficits by bone-marrow transplantation, and reached initial neurodegeneration stages at 12 months of age. Global cerebellar transcriptomics demonstrated ATM depletion to trigger upregulations in most neurotransmission and neuropeptide systems. Downregulated transcripts were found for the ATM interactome component Usp2, many non-coding RNAs, ataxia genes Itpr1, Grid2, immediate early genes and immunity factors. Allelic splice changes affected prominently neuropeptide machinery, e.g. Oprm1. Validation experiments with stressors were performed in human neuroblastoma cells, where ATM localized only to cytoplasm, similar to brain. Effect confirmation in SH-SY5Y cells occurred better after ATM depletion and osmotic stress better than nutrient / oxidative stress, rather than ATM kinase inhibition or DNA stressor bleomycin. Overall, we provide pioneer observations from a faithful A-T mouse model, which suggest general changes in synaptic and dense-core vesicle stress adaptation.
2023-10-24 | GSE241955 | GEO