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  1. Article ; Online: Mutations in the transcription factor FOXO1 mimic positive selection signals to promote germinal center B cell expansion and lymphomagenesis.

    Roberto, Mark P / Varano, Gabriele / Vinas-Castells, Rosa / Holmes, Antony B / Kumar, Rahul / Pasqualucci, Laura / Farinha, Pedro / Scott, David W / Dominguez-Sola, David

    Immunity

    2021  Volume 54, Issue 8, Page(s) 1807–1824.e14

    Abstract: The transcription factor forkhead box O1 (FOXO1), which instructs the dark zone program to direct germinal center (GC) polarity, is typically inactivated by phosphatidylinositol 3-kinase (PI3K) signals. Here, we investigated how FOXO1 mutations targeting ...

    Abstract The transcription factor forkhead box O1 (FOXO1), which instructs the dark zone program to direct germinal center (GC) polarity, is typically inactivated by phosphatidylinositol 3-kinase (PI3K) signals. Here, we investigated how FOXO1 mutations targeting this regulatory axis in GC-derived B cell non-Hodgkin lymphomas (B-NHLs) contribute to lymphomagenesis. Examination of primary B-NHL tissues revealed that FOXO1 mutations and PI3K pathway activity were not directly correlated. Human B cell lines bearing FOXO1 mutations exhibited hyperactivation of PI3K and Stress-activated protein kinase (SAPK)/Jun amino-terminal kinase (JNK) signaling, and increased cell survival under stress conditions as a result of alterations in FOXO1 transcriptional affinities and activation of transcriptional programs characteristic of GC-positive selection. When modeled in mice, FOXO1 mutations conferred competitive advantage to B cells in response to key T-dependent immune signals, disrupting GC homeostasis. FOXO1 mutant transcriptional signatures were prevalent in human B-NHL and predicted poor clinical outcomes. Thus, rather than enforcing FOXO1 constitutive activity, FOXO1 mutations enable co-option of GC-positive selection programs during the pathogenesis of GC-derived lymphomas.
    MeSH term(s) Animals ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; Cell Differentiation/genetics ; Cell Differentiation/immunology ; Cell Line ; Cell Proliferation/genetics ; Cell Survival/genetics ; Forkhead Box Protein O1/genetics ; Gene Expression Regulation/genetics ; Germinal Center/immunology ; HEK293 Cells ; Humans ; Lymphoma, B-Cell/genetics ; Lymphoma, B-Cell/pathology ; MAP Kinase Kinase 4/metabolism ; Mice ; Mice, Inbred C57BL ; Phosphatidylinositol 3-Kinases/metabolism ; Signal Transduction/genetics ; Signal Transduction/immunology
    Chemical Substances FOXO1 protein, human ; Forkhead Box Protein O1 ; Foxo1 protein, mouse ; MAP Kinase Kinase 4 (EC 2.7.12.2)
    Language English
    Publishing date 2021-08-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1217235-2
    ISSN 1097-4180 ; 1074-7613
    ISSN (online) 1097-4180
    ISSN 1074-7613
    DOI 10.1016/j.immuni.2021.07.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4227: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 69: Show issues

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  2. Article ; Online: Dynamic regulation of B cell complement signaling is integral to germinal center responses.

    Cumpelik, Arun / Heja, David / Hu, Yuan / Varano, Gabriele / Ordikhani, Farideh / Roberto, Mark P / He, Zhengxiang / Homann, Dirk / Lira, Sergio A / Dominguez-Sola, David / Heeger, Peter S

    Nature immunology

    2021  Volume 22, Issue 6, Page(s) 757–768

    Abstract: Maturation of B cells within germinal centers (GCs) generates diversified B cell pools and high-affinity B cell antigen receptors (BCRs) for pathogen clearance. Increased receptor affinity is achieved by iterative cycles of T cell-dependent, affinity- ... ...

    Abstract Maturation of B cells within germinal centers (GCs) generates diversified B cell pools and high-affinity B cell antigen receptors (BCRs) for pathogen clearance. Increased receptor affinity is achieved by iterative cycles of T cell-dependent, affinity-based B cell positive selection and clonal expansion by mechanisms hitherto incompletely understood. Here we found that, as part of a physiologic program, GC B cells repressed expression of decay-accelerating factor (DAF/CD55) and other complement C3 convertase regulators via BCL6, but increased the expression of C5b-9 inhibitor CD59. These changes permitted C3 cleavage on GC B cell surfaces without the formation of membrane attack complex and activated C3a- and C5a-receptor signals required for positive selection. Genetic disruption of this pathway in antigen-activated B cells by conditional transgenic DAF overexpression or deletion of C3a and C5a receptors limited the activation of mechanistic target of rapamycin (mTOR) in response to BCR-CD40 signaling, causing premature GC collapse and impaired affinity maturation. These results reveal that coordinated shifts in complement regulation within the GC provide crucial signals underlying GC B cell positive selection.
    MeSH term(s) Animals ; Animals, Genetically Modified ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; CD55 Antigens/genetics ; CD55 Antigens/metabolism ; CD59 Antigens/metabolism ; Cell Line, Tumor ; Clonal Hematopoiesis/immunology ; Complement Activation ; Complement C3a/metabolism ; Complement C5a/metabolism ; Germinal Center/cytology ; Germinal Center/immunology ; Germinal Center/metabolism ; Humans ; Lymphocyte Activation ; Mice ; Palatine Tonsil/cytology ; Palatine Tonsil/pathology ; Proto-Oncogene Proteins c-bcl-6/metabolism ; Receptor, Anaphylatoxin C5a/genetics ; Receptor, Anaphylatoxin C5a/metabolism ; Receptors, Antigen, B-Cell/metabolism ; Receptors, Complement/genetics ; Receptors, Complement/metabolism ; Signal Transduction/immunology ; TOR Serine-Threonine Kinases/metabolism
    Chemical Substances CD55 Antigens ; CD59 Antigens ; Proto-Oncogene Proteins c-bcl-6 ; Receptor, Anaphylatoxin C5a ; Receptors, Antigen, B-Cell ; Receptors, Complement ; complement C3a receptor ; Complement C3a (80295-42-7) ; Complement C5a (80295-54-1) ; MTOR protein, human (EC 2.7.1.1) ; mTOR protein, mouse (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2021-05-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2016987-5
    ISSN 1529-2916 ; 1529-2908
    ISSN (online) 1529-2916
    ISSN 1529-2908
    DOI 10.1038/s41590-021-00926-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5294: Show issues Location:
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    Zs.MG 42: Show issues

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  3. Article ; Online: Targeting the oncogene LSF with either the small molecule inhibitor FQI1 or siRNA causes mitotic delays with unaligned chromosomes, resulting in cell death or senescence.

    Willoughby, Jennifer L S / George, Kelly / Roberto, Mark P / Chin, Hang Gyeong / Stoiber, Patrick / Shin, Hyunjin / Pedamallu, Chandra Sekhar / Schaus, Scott E / Fitzgerald, Kevin / Shah, Jagesh / Hansen, Ulla

    BMC cancer

    2020  Volume 20, Issue 1, Page(s) 552

    Abstract: Background: The oncogene LSF (encoded by TFCP2) has been proposed as a novel therapeutic target for multiple cancers. LSF overexpression in patient tumors correlates with poor prognosis in particular for both hepatocellular carcinoma and colorectal ... ...

    Abstract Background: The oncogene LSF (encoded by TFCP2) has been proposed as a novel therapeutic target for multiple cancers. LSF overexpression in patient tumors correlates with poor prognosis in particular for both hepatocellular carcinoma and colorectal cancer. The limited treatment outcomes for these diseases and disappointing clinical results, in particular, for hepatocellular carcinoma in molecularly targeted therapies targeting cellular receptors and kinases, underscore the need for molecularly targeting novel mechanisms. LSF small molecule inhibitors, Factor Quinolinone Inhibitors (FQIs), have exhibited robust anti-tumor activity in multiple pre-clinical models, with no observable toxicity.
    Methods: To understand how the LSF inhibitors impact cancer cell proliferation, we characterized the cellular phenotypes that result from loss of LSF activity. Cell proliferation and cell cycle progression were analyzed, using HeLa cells as a model cancer cell line responsive to FQI1. Cell cycle progression was studied either by time lapse microscopy or by bulk synchronization of cell populations to ensure accuracy in interpretation of the outcomes. In order to test for biological specificity of targeting LSF by FQI1, results were compared after treatment with either FQI1 or siRNA targeting LSF.
    Results: Highly similar cellular phenotypes are observed upon treatments with FQI1 and siRNA targeting LSF. Along with similar effects on two cellular biomarkers, inhibition of LSF activity by either mechanism induced a strong delay or arrest prior to metaphase as cells progressed through mitosis, with condensed, but unaligned, chromosomes. This mitotic disruption in both cases resulted in improper cellular division leading to multiple outcomes: multi-nucleation, apoptosis, and cellular senescence.
    Conclusions: These data strongly support that cellular phenotypes observed upon FQI1 treatment are due specifically to the loss of LSF activity. Specific inhibition of LSF by either small molecules or siRNA results in severe mitotic defects, leading to cell death or senescence - consequences that are desirable in combating cancer. Taken together, these findings confirm that LSF is a promising target for cancer treatment. Furthermore, this study provides further support for developing FQIs or other LSF inhibitory strategies as treatment for LSF-related cancers with high unmet medical needs.
    MeSH term(s) Apoptosis/drug effects ; Apoptosis/genetics ; Benzodioxoles/pharmacology ; Benzodioxoles/therapeutic use ; Cell Cycle Checkpoints/drug effects ; Cell Cycle Checkpoints/genetics ; Cell Division/drug effects ; Cell Division/genetics ; Cellular Senescence/drug effects ; Cellular Senescence/genetics ; Chromosomes, Human/drug effects ; Chromosomes, Human/genetics ; Chromosomes, Human/metabolism ; DNA-Binding Proteins/antagonists & inhibitors ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Drug Screening Assays, Antitumor ; HeLa Cells ; Humans ; Intravital Microscopy ; Molecular Targeted Therapy/methods ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/pathology ; Quinolones/pharmacology ; Quinolones/therapeutic use ; RNA, Small Interfering/metabolism ; Time-Lapse Imaging ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/genetics ; Transcription Factors/metabolism
    Chemical Substances 8-(2-ethoxyphenyl)-7,8-dihydro-(1,3)dioxolo(4,5-g)quinolin-6(5H)-one ; Benzodioxoles ; DNA-Binding Proteins ; Quinolones ; RNA, Small Interfering ; TFCP2 protein, human ; Transcription Factors
    Language English
    Publishing date 2020-06-15
    Publishing country England
    Document type Journal Article ; Video-Audio Media
    ZDB-ID 2041352-X
    ISSN 1471-2407 ; 1471-2407
    ISSN (online) 1471-2407
    ISSN 1471-2407
    DOI 10.1186/s12885-020-07039-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma.

    Bollard, Julien / Miguela, Verónica / Ruiz de Galarreta, Marina / Venkatesh, Anu / Bian, C Billie / Roberto, Mark P / Tovar, Victoria / Sia, Daniela / Molina-Sánchez, Pedro / Nguyen, Christie B / Nakagawa, Shigeki / Llovet, Josep M / Hoshida, Yujin / Lujambio, Amaia

    Gut

    2016  Volume 66, Issue 7, Page(s) 1286–1296

    Abstract: Objective: Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast ... ...

    Abstract Objective: Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast cancer. RB1 is rarely mutated in HCC, suggesting that palbociclib could potentially be used for HCC therapy. Here, we provide a comprehensive characterisation of the efficacy of palbociclib in multiple preclinical models of HCC.
    Design: The effects of palbociclib on cell proliferation, cellular senescence and cell death were investigated in a panel of human liver cancer cell lines, in ex vivo human HCC samples, in a genetically engineered mouse model of liver cancer, and in human HCC xenografts in vivo. The mechanisms of intrinsic and acquired resistance to palbociclib were assessed in human liver cancer cell lines and human HCC samples by protein and gene expression analyses.
    Results: Palbociclib suppressed cell proliferation in human liver cancer cell lines by promoting a reversible cell cycle arrest. Intrinsic and acquired resistance to palbociclib was determined by loss of RB1. A signature of 'RB1 loss of function' was found in <30% of HCC samples. Palbociclib, alone or combined with sorafenib, the standard of care for HCC, impaired tumour growth in vivo and significantly increased survival.
    Conclusions: Palbociclib shows encouraging results in preclinical models of HCC and represents a novel therapeutic strategy for HCC treatment, alone or particularly in combination with sorafenib. Palbociclib could potentially benefit patients with RB1-proficient tumours, which account for 70% of all patients with HCC.
    MeSH term(s) Antineoplastic Combined Chemotherapy Protocols ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/pathology ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cellular Senescence/drug effects ; Drug Evaluation, Preclinical ; Humans ; Liver Neoplasms/drug therapy ; Liver Neoplasms/pathology ; Niacinamide/analogs & derivatives ; Niacinamide/pharmacology ; Phenylurea Compounds/pharmacology ; Piperazines/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Pyridines/pharmacology ; Retinoblastoma Binding Proteins/metabolism ; Ubiquitin-Protein Ligases/metabolism
    Chemical Substances Phenylurea Compounds ; Piperazines ; Protein Kinase Inhibitors ; Pyridines ; RB1 protein, human ; Retinoblastoma Binding Proteins ; Niacinamide (25X51I8RD4) ; sorafenib (9ZOQ3TZI87) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; palbociclib (G9ZF61LE7G)
    Language English
    Publishing date 2016-11-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80128-8
    ISSN 1468-3288 ; 0017-5749
    ISSN (online) 1468-3288
    ISSN 0017-5749
    DOI 10.1136/gutjnl-2016-312268
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 160: Show issues Location:
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