Recurrent alterations of TNFAIP3 (A20) in T-cell large granular lymphocytic leukemia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE69735 | GEO | 2016/06/12
SECONDARY ACCESSION(S): PRJNA286292
REPOSITORIES: GEO
Similar Datasets
Project description:We identified a novel recurrent genetic lesion in T-LGL. Mutations of the tumour suppressor gene TNFAIP3 causing amino-acid exchanges or protein truncations were seen in 3/39 cases (8%). RNA sequencing (Illumina HiSeq 2500) of 5 index patients with paired tumor and non-tumor samples.
2016-06-12 | E-GEOD-69735 | biostudies-arrayexpress
Project description:Enhancers affect gene expression and disease. Little is known about enhancers that regulate human disease-associated genes in their native chromosomal context in primary cells relevant for pathogenesis. We used a BAC transgenic approach combined with CRISPR- and recombineering-mediated genome editing to dissect enhancers that regulate human TNFAIP3/A20, which is tightly linked with autoimmune diseases, in vivo and in primary immune cells. >20 enhancers in the A20 superenhancer were redundant; A20 expression was regulated by a topologically associating subdomain (sub-TAD) that harbors 5 enhancers. Deletion of this sub- TAD enhanced inflammatory responses and autoantibody production, establishing its functional importance in vivo. We identified cell- and activation-specific enhancers within this sub-TAD, including a key role for an enhancer harboring a proposed causal SLE-associated SNV. These findings map genomic regions that regulate human A20 expression to prevent inflammatory pathology and autoimmunity, and provide a platform for causally linking enhancers and SNVs with disease phenotypes.
2017-11-16 | GSE104638 | GEO
Project description:To determine the protein expression of TNFAIP3 in synovium and to show the capability of 6q23 intergenic SNPs, associated with rheumatoid arthritis (RA) susceptibility, to influence TNFAIP3 gene transcription.Immunohistochemistry for TNFAIP3, NF-kB p65 and phosphorylated NF-kB p65 protein expression was performed in 6 RA knee joint synovium samples compared to 9 osteoarthritis (OA) samples. Luciferase reporter gene assays were used to examine the regulatory ability of RA associated SNP variants on TNFAIP3 promoter activity. Sense and antisense constructs were prepared for rs6920220 alleles, together with each of the 4 SNPs in r2=1 with it (rs6933404, rs2327832, rs6927172 and rs17264332), coupled to the TNFAIP3 promoter. Transient transfections were performed in a human T lymphoblastoid (CEMC7A) cell line. Bioinformatic software was utilised to prioritise SNPs for further investigation. Electrophoretic mobility shift assays (EMSA), using CEMC7A nuclear extracts, were conducted for the rs6927172 SNP alleles.TNFAIP3 protein expression was seen in the synovium samples and differential TNFAIP3 protein expression between RA vs. OA synoviocytes observed. Within RA synoviocytes TNFAIP3 expression is predominately cytoplasmic, whereas in OA its expression is strongly nuclear and cytoplasmic. For 3 of the 5 SNPs investigated (rs6920220, rs6933404, rs6927172) evidence of repressor activity of TNFAIP3 transcription was seen and EMSA data showed evidence of differential transcription factor binding to rs6927172 alleles.This is the first observation of TNFAIP3 protein expression in RA and OA synovium. In vitro analysis of 6q23 intergenic SNPs supports the possibility of the functional regulation of TNFAIP3.
| S-EPMC3093652 | biostudies-literature
Project description:Our results suggest that STAT3 can be activated independent of key oncogenic driver mutations in its SH2 domain in a subset of patients with large granular lymphocyte disorders. We examined the gene expression pattern in T-LGL leukemias compared to controls, and the impact of the presence of STAT3 mutations on the transcriptional regulation of a specific set of genes previously described.
2012-08-03 | GSE39838 | GEO
Project description:Genetic TNFAIP3 (A20) inactivation is a classical somatic lymphoma lesion and the genomic trait in haploinsufficiency of A20 (HA20). In a cohort of 33 HA20 patients, we show that heterozygous TNFAIP3 loss skews immune repertoires towards lymphocytes with classical self-reactive antigen receptors typically found in B and T cell lymphomas.
2023-07-28 | E-MTAB-12491 | biostudies-arrayexpress
Project description:To investigate the impact of A20 on testosterone synthesis in the context of age-related inflammation, we employed lentiviral constructs to establish TNFAIP3-overexpressing TM3 cell lines. Subsequently, we conducted gene expression profiling analysis using RNA-seq data obtained from both normal TM3 cells and TNFAIP3-overexpressing TM3 cells.
2023-10-28 | GSE237064 | GEO
Project description:A20, a negative regulator of NF-?B, has been implicated as a tumor suppressor gene in multiple types of B-cell lymphoma. AIDS-related lymphomas (ARLs) are high-grade B-cell lymphomas that are frequently associated with EBV infection. We examined a panel of ARLs for A20 alterations. FISH showed A20 deletion in 6 of 33 cases (18%). A20 mutations were found in 3 of 19 cases (16%), including 2 cases with deletions of the comple-mentary allele. Immunohistochemistry showed the absence of A20 protein in 7 of 55 samples (13%). In contrast to reports in Hodgkin lymphoma in which EBV infection and A20 alteration are mutually exclusive, A20 inactivation was observed in both EBV(+) and EBV(-) cases. The EBV latent membrane protein 1, which activates NF-?B, was not expressed in 12 of 13 cases with A20 loss. In ARLs loss of A20 may be an alternative mechanism of NF-?B activation in the absence of latent membrane protein 1 expression.
| S-EPMC3100694 | biostudies-literature
Project description:We identified novel recurrent genetic lesions in T-PLL affecting genes involved in JAK/STAT signaling (PTPRC), epigenetic regulation (PRDM2), or DNA damage repair (SAMHD1, PARP10, HERC1, HERC2). Mutations of the tumor suppressor gene SAMHD1 causing amino-acid exchanges or protein truncations as well as copy number variations in SAMHD1 were seen in 20% of cases.
2018-07-23 | GSE100844 | GEO
Project description:We identified novel recurrent genetic lesions in T-PLL affecting genes involved in JAK/STAT signaling (PTPRC), epigenetic regulation (PRDM2), or DNA damage repair (SAMHD1, PARP10, HERC1, HERC2). Mutations of the tumor suppressor gene SAMHD1 causing amino-acid exchanges or protein truncations as well as copy number variations in SAMHD1 were seen in 20% of cases.
2018-02-22 | GSE100882 | GEO
Project description:Background and methods: T-cell large granular lymphocytosis (T-LGL) is a lymphoproliferative disease usually presenting with cytopenia, and typically characterized by clonal expansion of terminally differentiated effector-memory cytotoxic T lymphocytes (CTLs). Conventional methods including flow cytometry and sequencing of Vb chains provided incomplete signature of TCR repertoire. Efforts to characterize transcriptome of clonal CTLs using whole peripheral blood or after enrichment of specific clones by flow cytometry have not provided satisfying resolution and scale due to heterogeneity among individual patients. We applied single cell TCR-sequencing coupled with single cell RNA sequencing to CD3+ T cells from a relatively large cohort (N=13) of T-LGL patients in a clinical protocol to prospectively test therapy with alemtuzumab in refractory disease, to characterize TCR repertoire and to define pathophysiologic mechanism at the single cell level, and to determine mechanisms of response and non-response to therapy. Results: T cells have less clonal diversity in T-LGL patients, compared with that in healthy donors. TCR repertoires in T-LGLL follow power law distribution but at a larger scale. There are no significant evidence of common TCR clonotypes among T-LGLL patients. TCR usage and T cell activation states shape T cell phenotypes. Cell survival and apoptosis gene programs are deregulated in T-LGL. Immunosuppressive treatment modulates clonality and gene expression in T-LGL. Conclusion: Our work complements and adds to previous modeling of T cell clonal expansion. Single cell sequencing of transcriptomes supports a theory of fluctuation in clone fitness, antigenic and environmental factors in concert with clone-specific and cell-specific germline and somatic genetic factors (HLA and STAT3).
2021-11-22 | GSE168859 | GEO