ARID1A Mutations Promote Immune Evasion of Follicular Lymphoma Through Reduced FAS-Mediated Apoptosis by Hindering RUNX3-ETS1 Cooperativity.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA957256 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The cell death receptor FAS and its ligand (FASLG) play a crucial role in the negative selection of B cells during the germinal center (GC) reaction. Failure to eliminate potentially harmful B cells can lead to the development B cell malignancies. Follicular lymphoma (FL) is a prototypic GC-derived B cell malignancy. Translocation and overexpression of antiapoptotic BCL2 is a hallmark of FL. Additional alterations have been shown to be clinically relevant, including mutations in ARID1A. ARID1A is part of the SWI/SNF nucleosome remodeling complex that regulates DNA accessibility (“openness”). However, the contribution of ARID1A mutations to the development and the biology of FL remains unclear. Based on a functional screen, we investigated the link between ARID1A mutations and FAS/FASLG-induced apoptosis in FL. We analyzed 151 diagnostic FL biopsies and found that ARID1A mutations were recurrent and mainly disruptive, with an overall frequency of 18%. Additionally, we observed that ARID1A mutant FL showed significantly lower FAS expression in the FL tumor cell population. Functional experiments in t(14;18)+ B lymphoma cells demonstrated that ARID1A is directly involved in the regulation of FAS, and ARID1A loss leads to decreased FAS protein and gene expression. However, ARID1A loss did not affect FAS promoter openness. Instead, we identified and experimentally validated a previously unknown co-transcriptional complex consisting of RUNX3 and ETS1 that regulates FAS expression, and ARID1A loss leads to reduced RUNX3 promotor openness and gene expression. The reduced FAS levels induced by ARID1A loss rendered lymphoma cells resistant to both soluble and T cell membrane-anchored FASLG-induced apoptosis. Furthermore, we observed an additional accumulation of ARID1A mutations in relapsed/refractory FL biopsies, indicating that we have identified a functionally and clinically relevant mechanism how FL cells can escape T cell mediated killing, which may also profoundly impact the efficacy of subsequent therapies, including CAR T cells.
2025-02-10 | GSE230036 | GEO
Project description:Cooperative DNA-binding by transcription factor (TF) proteins is critical for gene expression regulation in eukaryotes. In the human genome, many regulatory regions contain TF binding sites in close proximity to each other, which can facilitate cooperative interactions. However, binding site proximity does not necessarily imply cooperative binding, as two TFs could also bind independently to each of their neighboring target sites. Currently, the rules that drive cooperative versus independent binding of TFs to neighboring sites are not well understood. In addition, it is oftentimes difficult to infer direct cooperativity between TFs from existing DNA-binding data. Here, we show that in vitro binding assays using DNA libraries of a few thousand genomic sequences with putative cooperative TF binding events can be used to develop accurate models of cooperativity and to gain insights into cooperative binding mechanisms. Using human factors ETS1 and RUNX1 as our case study, we show that the distance and orientation between ETS1 sites are critical determinants of cooperative ETS1-ETS1 binding, while cooperative ETS1- RUNX1 interactions show more flexibility in distance and orientation and can be accurately predicted based on binding affinity and the sequence/shape features of the binding sites. The approach described here, combining custom experimental design with machine learning modeling, can be easily applied to study the cooperative DNA-binding patterns of any TFs.
2023-07-30 | GSE171732 | GEO
Project description:Cooperative DNA-binding by transcription factor (TF) proteins is critical for gene expression regulation in eukaryotes. In the human genome, many regulatory regions contain TF binding sites in close proximity to each other, which can facilitate cooperative interactions. However, binding site proximity does not necessarily imply cooperative binding, as two TFs could also bind independently to each of their neighboring target sites. Currently, the rules that drive cooperative versus independent binding of TFs to neighboring sites are not well understood. In addition, it is oftentimes difficult to infer direct cooperativity between TFs from existing DNA-binding data. Here, we show that in vitro binding assays using DNA libraries of a few thousand genomic sequences with putative cooperative TF binding events can be used to develop accurate models of cooperativity and to gain insights into cooperative binding mechanisms. Using human factors ETS1 and RUNX1 as our case study, we show that the distance and orientation between ETS1 sites are critical determinants of cooperative ETS1-ETS1 binding, while cooperative ETS1- RUNX1 interactions show more flexibility in distance and orientation and can be accurately predicted based on binding affinity and the sequence/shape features of the binding sites. The approach described here, combining custom experimental design with machine learning modeling, can be easily applied to study the cooperative DNA-binding patterns of any TFs.
2023-07-30 | GSE171734 | GEO
Project description:Cellular binary fate decisions require the progeny to silence genes associated with the alternative fate. The major subsets of alpha:beta T cells have been extensively studied as a model system for fate decisions. While the transcription factor RUNX3 is required for the initiation of Cd4 silencing in CD8 T cell progenitors, it is not required to maintain the silencing of Cd4 and other helper T lineage genes. The other runt domain containing protein, RUNX1, silences Cd4 in an earlier T cell progenitor, but this silencing is reversed whereas the gene silencing after RUNX3 expression is not reverse. Therefore, we hypothesized that RUNX3 and not RUNX1 recruits other factors that maintains the silencing of helper T lineage genes in CD8 T cells. To this end, we performed a proteomics screen of RUNX1 and RUNX3 to determine candidate silencing factors.
2019-11-12 | PXD007511 | Pride
Project description:Ewing sarcoma is an aggressive pediatric small round cell tumor that predominantly occurs in bone. Approximately 85% of Ewing sarcomas harbor the EWS/FLI fusion protein, which arises from a chromosomal translocation, t(11:22)(q24:q12). EWS/FLI interacts with numerous lineage-essential transcription factors to maintain mesenchymal progenitors in an undifferentiated state. We previously showed that EWS/FLI binds the osteogenic transcription factor RUNX2 and prevents osteoblast differentiation. In this study, we investigated the role of another Runt-domain protein, RUNX3, in Ewing sarcoma. RUNX3 participates in mesenchymal-derived bone formation and is a context dependent tumor suppressor and oncogene. RUNX3 was detected in all Ewing sarcoma cells examined, whereas RUNX2 was detected in only 73% of specimens. Like RUNX2, RUNX3 binds to EWS/FLI via its Runt domain. EWS/FLI prevented RUNX3 from activating the transcription of a RUNX-responsive reporter, p6OSE2. Stable suppression of RUNX3 expression in the Ewing sarcoma cell line A673 delayed colony growth in anchorage independent soft agar assays and reversed expression of EWS/FLI-responsive genes. These results demonstrate an important role for RUNX3 in Ewing sarcoma. RNA-seq to compare transcriptiome of control A673 ewing sarcoma cells stably expression a non-target or RUNX3 shRNA
2014-05-01 | E-GEOD-56900 | biostudies-arrayexpress
Project description:To gain insight into the role of Runx3 in TrkC neurons we performed RNA-seq on E11.5 TrkC neurons isolated from cervical ganglia of Runx3-P2+/- and Runx3-P2-/- mice
2016-11-20 | GSE81140 | GEO
Project description:Expression profiling of Rag2-deficient Ets1++ and Rag2-deficient Ets1-- mature NK cells and WT bone marrow progenitors, WT T cells, and WT Pro B cells WT Hematopoietic progenitors, CD4 T cells, Pro B cells, and WT and Ets1-deficient NK cells were FACs sorted. RNA was subsequently extracted, labelled, and hybridized to Affymetrix microarrays. The goal if this experiment was to identify Ets1 dependent genes in NK cells
2012-08-09 | E-GEOD-37301 | biostudies-arrayexpress
Project description:NK cells are innate immune cells that recognize and kill foreign, virally-infected and tumor cells without the need for prior immunization. NK expansion following viral infection is IL-2 or IL-15-dependent. To identify Runx3 responsive genes, NK cells were isolated from spleen of WT and Runx3-/- mice . Six samples (3 WT and 3 Runx3-/-) of freshly isolated NK cells (resting) were separately obtained from individual mice.
2013-11-18 | E-GEOD-50123 | biostudies-arrayexpress
Project description:CD8+T cells are immune cells that recognize foreign antigens on infected and tumor cells, leading to cytokine-dependent expansion and activation of cytotoxicity towards the targets. To identify Runx3 responsive genes, CD8+ T cells were isolated from spleen of WT and Runx3-/- mice . Six samples (3 WT and 3 Runx3-/-) of freshly isolated CD8+ T cells (resting) were separately obtained from individual mice.
2013-11-18 | E-GEOD-50119 | biostudies-arrayexpress