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ABSTRACT:
PROVIDER: PRJNA966144 | ENA |
REPOSITORIES: ENA
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Project description:ARID1A Mutations Promote Immune Evasion of Follicular Lymphoma Through Reduced FAS-Mediated Apoptosis by Hindering RUNX3-ETS1 Cooperativity.
| PRJNA957256 | ENA
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:Runt-related transcription factor 3 (RUNX3) has been described as a tumor suppressor for gastric cancer and other solid malignancies. Despite its key role in physiological T-cell differentiation, there is rare information on its relevance for the development of human T-cell lymphoma or leukemia. Here we show that alterations of RUNX3 by either heterozygous deletion or methylation of its distal promoter can be observed in the tumor cells of 15/21 (71%) patients suffering from Sézary Syndrome (SS), an aggressive variant of cutaneous T-cell lymphoma. In consequence, mRNA levels of RUNX3/p46, the long isoform of RUNX3 – controlled by the proximal promoter – are significantly lower in SS tumor cells. Re-expression of RUNX3/p46 promotes apoptosis and slows down proliferation in a RUNX3/p46low cell line of cutaneous T-cell lymphoma. By this we present the first evidence that RUNX3 can act as a tumor suppressor in a human T-cell malignancy and suggest that this effect is predominantly mediated through the long isoform of this transcription factor, which has not been in the focus of previous studies.
2015-10-01 | GSE63013 | GEO
Project description:ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. Our study shows that ARID1A orchestrates B-cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD signaling. The absence of ARID1A tilts GC cell-fate towards immature IgM+CD80-PDL2- memory B-cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas in mice. Remarkably, follicular lymphoma patients with ARID1A-inactivating mutations preferentially display an immature memory B-cell-like state with increased transformation risk to aggressive disease. These observations offer mechanistic understanding into the emergence of both indolent and aggressive lymphomas in ARID1A-mutant patients through formation of immature memory-like clonal precursors. Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4 inhibition, paving the way for potential precision therapy for high-risk patients.
2024-02-02 | GSE254595 | GEO
Project description:ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. Our study shows that ARID1A orchestrates B-cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD signaling. The absence of ARID1A tilts GC cell-fate towards immature IgM+CD80-PDL2- memory B-cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas in mice. Remarkably, follicular lymphoma patients with ARID1A-inactivating mutations preferentially display an immature memory B-cell-like state with increased transformation risk to aggressive disease. These observations offer mechanistic understanding into the emergence of both indolent and aggressive lymphomas in ARID1A-mutant patients through formation of immature memory-like clonal precursors. Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4 inhibition, paving the way for potential precision therapy for high-risk patients.
2024-02-02 | GSE254594 | GEO
Project description:ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. Our study shows that ARID1A orchestrates B-cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD signaling. The absence of ARID1A tilts GC cell-fate towards immature IgM+CD80-PDL2- memory B-cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas in mice. Remarkably, follicular lymphoma patients with ARID1A-inactivating mutations preferentially display an immature memory B-cell-like state with increased transformation risk to aggressive disease. These observations offer mechanistic understanding into the emergence of both indolent and aggressive lymphomas in ARID1A-mutant patients through formation of immature memory-like clonal precursors. Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4 inhibition, paving the way for potential precision therapy for high-risk patients.
2024-02-02 | GSE254593 | GEO
Project description:ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. Our study shows that ARID1A orchestrates B-cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD signaling. The absence of ARID1A tilts GC cell-fate towards immature IgM+CD80-PDL2- memory B-cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas in mice. Remarkably, follicular lymphoma patients with ARID1A-inactivating mutations preferentially display an immature memory B-cell-like state with increased transformation risk to aggressive disease. These observations offer mechanistic understanding into the emergence of both indolent and aggressive lymphomas in ARID1A-mutant patients through formation of immature memory-like clonal precursors. Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4 inhibition, paving the way for potential precision therapy for high-risk patients.
2024-02-02 | GSE254591 | GEO
Project description:ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. Our study shows that ARID1A orchestrates B-cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD40 signaling. The absence of ARID1A tilts GC cell-fate towards immature IgM+CD80-PDL2- memory B-cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas in mice. Remarkably, follicular lymphoma patients with ARID1A-inactivating mutations preferentially display an immature memory B-cell-like state with increased transformation risk to aggressive disease. These observations offer mechanistic understanding into the emergence of both indolent and aggressive lymphomas in ARID1A-mutant patients through formation of immature memory-like clonal precursors. Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4 inhibition, paving the way for potential precision therapy for high-risk patients.
2024-02-02 | GSE237987 | GEO
Project description:ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. Our study shows that ARID1A orchestrates B-cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD signaling. The absence of ARID1A tilts GC cell-fate towards immature IgM+CD80-PDL2- memory B-cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas in mice. Remarkably, follicular lymphoma patients with ARID1A-inactivating mutations preferentially display an immature memory B-cell-like state with increased transformation risk to aggressive disease. These observations offer mechanistic understanding into the emergence of both indolent and aggressive lymphomas in ARID1A-mutant patients through formation of immature memory-like clonal precursors. Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4 inhibition, paving the way for potential precision therapy for high-risk patients.
2024-03-22 | GSE262094 | GEO
Project description:ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. Our study shows that ARID1A orchestrates B-cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD signaling. The absence of ARID1A tilts GC cell-fate towards immature IgM+CD80-PDL2- memory B-cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas in mice. Remarkably, follicular lymphoma patients with ARID1A-inactivating mutations preferentially display an immature memory B-cell-like state with increased transformation risk to aggressive disease. These observations offer mechanistic understanding into the emergence of both indolent and aggressive lymphomas in ARID1A-mutant patients through formation of immature memory-like clonal precursors. Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4 inhibition, paving the way for potential precision therapy for high-risk patients.
2024-03-22 | GSE262093 | GEO