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  1. Artikel ; Online: PRMT1 acts as a suppressor of MHC-I and anti-tumor immunity.

    Djajawi, Tirta M / Pijpers, Lizzy / Srivaths, Akash / Chisanga, David / Chan, Kok Fei / Hogg, Simon J / Neil, Liam / Rivera, Sarahi Mendoza / Bartonicek, Nenad / Ellis, Sarah L / Lim Kam Sian, Terry C C / Faridi, Pouya / Liao, Yang / Pal, Bhupinder / Behren, Andreas / Shi, Wei / Vervoort, Stephin J / Johnstone, Ricky W / Kearney, Conor J

    Cell reports

    2024  Band 43, Heft 3, Seite(n) 113831

    Abstract: Cancer immunotherapies have demonstrated remarkable success; however, the majority of patients do not respond or develop resistance. Here, we conduct epigenetic gene-targeted CRISPR-Cas9 screens to identify epigenomic factors that limit ... ...

    Abstract Cancer immunotherapies have demonstrated remarkable success; however, the majority of patients do not respond or develop resistance. Here, we conduct epigenetic gene-targeted CRISPR-Cas9 screens to identify epigenomic factors that limit CD8
    Mesh-Begriff(e) Humans ; CD8-Positive T-Lymphocytes/metabolism ; Protein-Arginine N-Methyltransferases/genetics ; Protein-Arginine N-Methyltransferases/metabolism ; Histocompatibility Antigens Class I/genetics ; Immunity, Cellular ; Interferon-gamma/metabolism ; Melanoma/pathology ; Repressor Proteins/genetics ; Repressor Proteins/metabolism
    Chemische Substanzen Protein-Arginine N-Methyltransferases (EC 2.1.1.319) ; Histocompatibility Antigens Class I ; Interferon-gamma (82115-62-6) ; PRMT1 protein, human (EC 2.1.1.319) ; Repressor Proteins
    Sprache Englisch
    Erscheinungsdatum 2024-02-23
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2024.113831
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia.

    So, Joan / Lewis, Alexander C / Smith, Lorey K / Stanley, Kym / Franich, Rheana / Yoannidis, David / Pijpers, Lizzy / Dominguez, Pilar / Hogg, Simon J / Vervoort, Stephin J / Brown, Fiona C / Johnstone, Ricky W / McDonald, Gabrielle / Ulanet, Danielle B / Murtie, Josh / Gruber, Emily / Kats, Lev M

    EMBO molecular medicine

    2022  Band 14, Heft 7, Seite(n) e15203

    Abstract: The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins, and phospholipids. DHODH ... ...

    Abstract The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins, and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anticancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein, we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) and has potent and selective activity against multiple AML subtypes. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.
    Mesh-Begriff(e) Dihydroorotate Dehydrogenase ; Enzyme Inhibitors/pharmacology ; Humans ; Leukemia, Myeloid, Acute ; Oxidoreductases Acting on CH-CH Group Donors/metabolism ; Protein Biosynthesis ; Pyrimidines/pharmacology
    Chemische Substanzen Dihydroorotate Dehydrogenase ; Enzyme Inhibitors ; Pyrimidines ; Oxidoreductases Acting on CH-CH Group Donors (EC 1.3.-)
    Sprache Englisch
    Erscheinungsdatum 2022-05-06
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2467145-9
    ISSN 1757-4684 ; 1757-4676
    ISSN (online) 1757-4684
    ISSN 1757-4676
    DOI 10.15252/emmm.202115203
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: SUGAR-seq enables simultaneous detection of glycans, epitopes, and the transcriptome in single cells.

    Kearney, Conor J / Vervoort, Stephin J / Ramsbottom, Kelly M / Todorovski, Izabela / Lelliott, Emily J / Zethoven, Magnus / Pijpers, Lizzy / Martin, Ben P / Semple, Timothy / Martelotto, Luciano / Trapani, Joseph A / Parish, Ian A / Scott, Nichollas E / Oliaro, Jane / Johnstone, Ricky W

    Science advances

    2021  Band 7, Heft 8

    Abstract: Multimodal single-cell RNA sequencing enables the precise mapping of transcriptional and phenotypic features of cellular differentiation states but does not allow for simultaneous integration of critical posttranslational modification data. Here, we ... ...

    Abstract Multimodal single-cell RNA sequencing enables the precise mapping of transcriptional and phenotypic features of cellular differentiation states but does not allow for simultaneous integration of critical posttranslational modification data. Here, we describe SUrface-protein Glycan And RNA-seq (SUGAR-seq), a method that enables detection and analysis of N-linked glycosylation, extracellular epitopes, and the transcriptome at the single-cell level. Integrated SUGAR-seq and glycoproteome analysis identified tumor-infiltrating T cells with unique surface glycan properties that report their epigenetic and functional state.
    Sprache Englisch
    Erscheinungsdatum 2021-02-19
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.abe3610
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Natural Killer Cells Suppress T Cell-Associated Tumor Immune Evasion.

    Freeman, Andrew J / Vervoort, Stephin J / Ramsbottom, Kelly M / Kelly, Madison J / Michie, Jessica / Pijpers, Lizzy / Johnstone, Ricky W / Kearney, Conor J / Oliaro, Jane

    Cell reports

    2019  Band 28, Heft 11, Seite(n) 2784–2794.e5

    Abstract: Despite the clinical success of cancer immunotherapies, the majority of patients fail to respond or develop resistance through disruption of pathways that promote neo-antigen presentation on MHC I molecules. Here, we conducted a series of unbiased, ... ...

    Abstract Despite the clinical success of cancer immunotherapies, the majority of patients fail to respond or develop resistance through disruption of pathways that promote neo-antigen presentation on MHC I molecules. Here, we conducted a series of unbiased, genome-wide CRISPR/Cas9 screens to identify genes that limit natural killer (NK) cell anti-tumor activity. We identified that genes associated with antigen presentation and/or interferon-γ (IFN-γ) signaling protect tumor cells from NK cell killing. Indeed, Jak1-deficient melanoma cells were sensitized to NK cell killing through attenuated NK cell-derived IFN-γ-driven transcriptional events that regulate MHC I expression. Importantly, tumor cells that became resistant to T cell killing through enrichment of MHC I-deficient clones were highly sensitive to NK cell killing. Taken together, we reveal the genes targeted by tumor cells to drive checkpoint blockade resistance but simultaneously increase their vulnerability to NK cells, unveiling NK cell-based immunotherapies as a strategy to antagonize tumor immune escape.
    Mesh-Begriff(e) Animals ; Antigen Presentation/genetics ; CRISPR-Cas Systems ; Cell Line, Tumor ; Coculture Techniques ; Cytotoxicity, Immunologic ; Female ; Gene Ontology ; Histocompatibility Antigens Class I/metabolism ; Humans ; Immunotherapy ; Interferon-gamma/genetics ; Interferon-gamma/metabolism ; Janus Kinase 1/genetics ; Janus Kinase 1/metabolism ; Killer Cells, Natural/immunology ; Male ; Melanoma/genetics ; Melanoma/immunology ; Melanoma/metabolism ; Melanoma/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Perforin/genetics ; Perforin/metabolism ; T-Lymphocytes/immunology ; Transplantation, Heterologous ; Tumor Escape/genetics ; Tumor Escape/immunology
    Chemische Substanzen Histocompatibility Antigens Class I ; Perforin (126465-35-8) ; Interferon-gamma (82115-62-6) ; Janus Kinase 1 (EC 2.7.10.2)
    Sprache Englisch
    Erscheinungsdatum 2019-09-20
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2019.08.017
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: Tumor immune evasion arises through loss of TNF sensitivity.

    Kearney, Conor J / Vervoort, Stephin J / Hogg, Simon J / Ramsbottom, Kelly M / Freeman, Andrew J / Lalaoui, Najoua / Pijpers, Lizzy / Michie, Jessica / Brown, Kristin K / Knight, Deborah A / Sutton, Vivien / Beavis, Paul A / Voskoboinik, Ilia / Darcy, Phil K / Silke, John / Trapani, Joseph A / Johnstone, Ricky W / Oliaro, Jane

    Science immunology

    2018  Band 3, Heft 23

    Abstract: Immunotherapy has revolutionized outcomes for cancer patients, but the mechanisms of resistance remain poorly defined. We used a series of whole-genome clustered regularly interspaced short palindromic repeat (CRISPR)-based screens performed in vitro and ...

    Abstract Immunotherapy has revolutionized outcomes for cancer patients, but the mechanisms of resistance remain poorly defined. We used a series of whole-genome clustered regularly interspaced short palindromic repeat (CRISPR)-based screens performed in vitro and in vivo to identify mechanisms of tumor immune evasion from cytotoxic lymphocytes [CD8
    Mesh-Begriff(e) Animals ; Antigen Presentation ; CD8-Positive T-Lymphocytes/immunology ; Cell Line, Tumor ; Interferon-gamma/immunology ; Killer Cells, Natural/immunology ; Mice ; Tumor Escape/immunology ; Tumor Necrosis Factor-alpha/immunology
    Chemische Substanzen Tumor Necrosis Factor-alpha ; Interferon-gamma (82115-62-6)
    Sprache Englisch
    Erscheinungsdatum 2018-11-12
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2470-9468
    ISSN (online) 2470-9468
    DOI 10.1126/sciimmunol.aar3451
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel: Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition

    Hogg, Simon J / Motorna, Olga / Cluse, Leonie A / Johanson, Timothy M / Coughlan, Hannah D / Raviram, Ramya / Myers, Robert M / Costacurta, Matteo / Todorovski, Izabela / Pijpers, Lizzy / Bjelosevic, Stefan / Williams, Tobias / Huskins, Shannon N / Kearney, Conor J / Devlin, Jennifer R / Fan, Zheng / Jabbari, Jafar S / Martin, Ben P / Fareh, Mohamed /
    Kelly, Madison J / Dupéré-Richer, Daphné / Sandow, Jarrod J / Feran, Breon / Knight, Deborah / Khong, Tiffany / Spencer, Andrew / Harrison, Simon J / Gregory, Gareth / Wickramasinghe, Vihandha O / Webb, Andrew I / Taberlay, Phillippa C / Bromberg, Kenneth D / Lai, Albert / Papenfuss, Anthony T / Smyth, Gordon K / Allan, Rhys S / Licht, Jonathan D / Landau, Dan A / Abdel-Wahab, Omar / Shortt, Jake / Vervoort, Stephin J / Johnstone, Ricky W

    Molecular cell. 2021 May 20, v. 81, no. 10

    2021  

    Abstract: To separate causal effects of histone acetylation on chromatin accessibility and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP in ... ...

    Abstract To separate causal effects of histone acetylation on chromatin accessibility and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP in hematological malignancies. We found that catalytic P300/CBP inhibition dynamically perturbs steady-state acetylation kinetics and suppresses oncogenic transcriptional networks in the absence of changes to chromatin accessibility. CRISPR-Cas9 screening identified NCOR1 and HDAC3 transcriptional co-repressors as the principal antagonists of P300/CBP by counteracting acetylation turnover kinetics. Finally, deacetylation of H3K27 provides nucleation sites for reciprocal methylation switching, a feature that can be exploited therapeutically by concomitant KDM6A and P300/CBP inhibition. Overall, this study indicates that the steady-state histone acetylation-methylation equilibrium functions as a molecular rheostat governing cellular transcription that is amenable to therapeutic exploitation as an anti-cancer regimen.
    Schlagwörter CRISPR-Cas systems ; acetylation ; chromatin ; epigenome ; histones ; lysine N-acetyltransferase ; methylation ; therapeutics ; transcription (genetics) ; transcriptomics
    Sprache Englisch
    Erscheinungsverlauf 2021-0520
    Umfang p. 2183-2200.e13.
    Erscheinungsort Elsevier Inc.
    Dokumenttyp Artikel
    Anmerkung NAL-AP-2-clean
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2021.04.015
    Datenquelle NAL Katalog (AGRICOLA)

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  7. Artikel ; Online: Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition.

    Hogg, Simon J / Motorna, Olga / Cluse, Leonie A / Johanson, Timothy M / Coughlan, Hannah D / Raviram, Ramya / Myers, Robert M / Costacurta, Matteo / Todorovski, Izabela / Pijpers, Lizzy / Bjelosevic, Stefan / Williams, Tobias / Huskins, Shannon N / Kearney, Conor J / Devlin, Jennifer R / Fan, Zheng / Jabbari, Jafar S / Martin, Ben P / Fareh, Mohamed /
    Kelly, Madison J / Dupéré-Richer, Daphné / Sandow, Jarrod J / Feran, Breon / Knight, Deborah / Khong, Tiffany / Spencer, Andrew / Harrison, Simon J / Gregory, Gareth / Wickramasinghe, Vihandha O / Webb, Andrew I / Taberlay, Phillippa C / Bromberg, Kenneth D / Lai, Albert / Papenfuss, Anthony T / Smyth, Gordon K / Allan, Rhys S / Licht, Jonathan D / Landau, Dan A / Abdel-Wahab, Omar / Shortt, Jake / Vervoort, Stephin J / Johnstone, Ricky W

    Molecular cell

    2021  Band 81, Heft 10, Seite(n) 2183–2200.e13

    Abstract: To separate causal effects of histone acetylation on chromatin accessibility and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP in ... ...

    Abstract To separate causal effects of histone acetylation on chromatin accessibility and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP in hematological malignancies. We found that catalytic P300/CBP inhibition dynamically perturbs steady-state acetylation kinetics and suppresses oncogenic transcriptional networks in the absence of changes to chromatin accessibility. CRISPR-Cas9 screening identified NCOR1 and HDAC3 transcriptional co-repressors as the principal antagonists of P300/CBP by counteracting acetylation turnover kinetics. Finally, deacetylation of H3K27 provides nucleation sites for reciprocal methylation switching, a feature that can be exploited therapeutically by concomitant KDM6A and P300/CBP inhibition. Overall, this study indicates that the steady-state histone acetylation-methylation equilibrium functions as a molecular rheostat governing cellular transcription that is amenable to therapeutic exploitation as an anti-cancer regimen.
    Mesh-Begriff(e) Acetylation ; Biocatalysis ; Cell Line ; Chromatin/metabolism ; Co-Repressor Proteins/metabolism ; Conserved Sequence ; Evolution, Molecular ; Gene Regulatory Networks ; Genome ; Histone Deacetylases/metabolism ; Histones/metabolism ; Humans ; Kinetics ; Methylation ; Models, Biological ; Oncogenes ; RNA Polymerase II/metabolism ; Transcription, Genetic ; p300-CBP Transcription Factors/metabolism
    Chemische Substanzen Chromatin ; Co-Repressor Proteins ; Histones ; p300-CBP Transcription Factors (EC 2.3.1.48) ; RNA Polymerase II (EC 2.7.7.-) ; Histone Deacetylases (EC 3.5.1.98) ; histone deacetylase 3 (EC 3.5.1.98)
    Sprache Englisch
    Erscheinungsdatum 2021-05-21
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2021.04.015
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Verfügbar in ZB MED Köln/Königswinter

    Zs.A 5055: Hefte anzeigen Standort:
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