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  1. Article ; Online: Identification of a novel form of caspase-independent cell death triggered by BH3-mimetics in diffuse large B-cell lymphoma cell lines.

    Yildirim, Nahide / Sarojam, Lakshmi / Smith, Victoria M / Pieper, Nadja M / Anders, Marius / Jackson, Ross A / Fuhrmann, Dominik C / Särchen, Vinzenz / Brücher, Daniela / Weigert, Andreas / Dyer, Martin J S / Vogler, Meike

    Cell death & disease

    2024  Volume 15, Issue 4, Page(s) 266

    Abstract: BH3-mimetics represent promising anti-cancer agents in tumors that rely on the anti-apoptotic function of B-Cell Lymphoma 2 (BCL2) proteins, particularly in leukemia and lymphoma cells primed for apoptosis. Mechanistically, BH3-mimetics may displace pro- ... ...

    Abstract BH3-mimetics represent promising anti-cancer agents in tumors that rely on the anti-apoptotic function of B-Cell Lymphoma 2 (BCL2) proteins, particularly in leukemia and lymphoma cells primed for apoptosis. Mechanistically, BH3-mimetics may displace pro-apoptotic binding partners thus inducing BAX/BAK-mediated mitochondrial permeabilization followed by cytochrome c release, activation of the caspase cascade and apoptosis. Here, we describe a novel mode of caspase-independent cell death (CICD) induced by BH3-mimetics in a subset of diffuse large B-cell lymphoma (DLBCL) cells. Of note, rather than occurring via necroptosis, CICD induced immediately after mitochondrial permeabilization was associated with transcriptional reprogramming mediated by activation of c-Jun N-terminal Kinase (JNK) signaling and Activator Protein 1 (AP1). Thereby, CICD resulted in the JNK/AP1-mediated upregulation of inflammatory chemokines and increased migration of cytotoxic Natural Killer (NK) cells. Taken together, our study describes a novel mode of CICD triggered by BH3-mimetics that may alter the immune response towards dying cells.
    MeSH term(s) Humans ; bcl-2-Associated X Protein/metabolism ; bcl-2 Homologous Antagonist-Killer Protein/metabolism ; Apoptosis ; Antineoplastic Agents/pharmacology ; Caspases ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Cell Line ; Proto-Oncogene Proteins c-bcl-2/metabolism
    Chemical Substances bcl-2-Associated X Protein ; bcl-2 Homologous Antagonist-Killer Protein ; Antineoplastic Agents ; Caspases (EC 3.4.22.-) ; Proto-Oncogene Proteins c-bcl-2
    Language English
    Publishing date 2024-04-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-024-06652-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Increased MCL1 dependency leads to new applications of BH3-mimetics in drug-resistant neuroblastoma.

    Jacob, Maureen / Wiedemann, Sara / Brücher, Daniela / Pieper, Nadja M / Birkhold, Moni / Särchen, Vinzenz / Jeroch, Jan / Demes, Melanie C / Gretser, Steffen / Braun, Yannick / Gradhand, Elise / Rothweiler, Florian / Michaelis, Martin / Cinatl, Jindrich / Vogler, Meike

    British journal of cancer

    2023  Volume 129, Issue 10, Page(s) 1667–1678

    Abstract: Background: Neuroblastoma is a paediatric cancer that is characterised by poor prognosis for chemoresistant disease, highlighting the need for better treatment options. Here, we asked whether BH3-mimetics inhibiting BCL2 proteins may eliminate ... ...

    Abstract Background: Neuroblastoma is a paediatric cancer that is characterised by poor prognosis for chemoresistant disease, highlighting the need for better treatment options. Here, we asked whether BH3-mimetics inhibiting BCL2 proteins may eliminate chemoresistant neuroblastoma cells.
    Methods: We utilised cisplatin-adapted neuroblastoma cell lines as well as patient tissues before and after relapse to study alterations of BCL2 proteins upon chemoresistance.
    Results: In a direct comparison of cisplatin-resistant cells we identified a prominent loss of sensitivity to BCL2/BCL-X
    Conclusions: These data highlight that the application of BH3-mimetics may differ between first line treatment and relapsed disease. Combination of NK cell-based immunotherapy with BH3-mimetics may further increase killing of chemoresistant neuroblastoma, outlining a new treatment strategy for relapsed neuroblastoma.
    MeSH term(s) Child ; Humans ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Proto-Oncogene Proteins/metabolism ; Cisplatin/pharmacology ; Cell Line, Tumor ; Neoplasm Recurrence, Local/drug therapy ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Neuroblastoma/drug therapy ; Antineoplastic Agents/pharmacology ; Apoptosis
    Chemical Substances Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins ; Cisplatin (Q20Q21Q62J) ; Proto-Oncogene Proteins c-bcl-2 ; Antineoplastic Agents ; MCL1 protein, human
    Language English
    Publishing date 2023-09-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80075-2
    ISSN 1532-1827 ; 0007-0920
    ISSN (online) 1532-1827
    ISSN 0007-0920
    DOI 10.1038/s41416-023-02430-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.142: Show issues Location:
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  3. Article ; Online: Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma.

    Smith, Victoria M / Dietz, Anna / Henz, Kristina / Bruecher, Daniela / Jackson, Ross / Kowald, Lisa / van Wijk, Sjoerd J L / Jayne, Sandrine / Macip, Salvador / Fulda, Simone / Dyer, Martin J S / Vogler, Meike

    Haematologica

    2019  Volume 105, Issue 8, Page(s) 2150–2163

    Abstract: The BCL-2-specific inhibitor, ABT-199 (venetoclax) has exhibited remarkable clinical activity in nearly all cases of chronic lymphocytic leukemia. In contrast, responses are usually much less in diffuse large B-cell lymphoma (DLBCL), despite high level ... ...

    Abstract The BCL-2-specific inhibitor, ABT-199 (venetoclax) has exhibited remarkable clinical activity in nearly all cases of chronic lymphocytic leukemia. In contrast, responses are usually much less in diffuse large B-cell lymphoma (DLBCL), despite high level expression of BCL-2 in over 40% of cases, indicating that co-expression of related anti-apoptotic BCL-2 family proteins may limit the activity of ABT-199. We have investigated the roles of BCL-2 proteins in DLBCL cells using a panel of specific BCL-2 homology 3 (BH3)-mimetics and identified subgroups of these cells that exhibited marked and specific dependency on either BCL-2, BCL-X
    MeSH term(s) Apoptosis ; Humans ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Lymphoma, Large B-Cell, Diffuse/genetics ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2/genetics ; bcl-2 Homologous Antagonist-Killer Protein/genetics ; bcl-X Protein/genetics
    Chemical Substances MCL1 protein, human ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2 ; bcl-2 Homologous Antagonist-Killer Protein ; bcl-X Protein
    Language English
    Publishing date 2019-10-10
    Publishing country Italy
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2333-4
    ISSN 1592-8721 ; 0017-6567 ; 0390-6078
    ISSN (online) 1592-8721
    ISSN 0017-6567 ; 0390-6078
    DOI 10.3324/haematol.2019.220525
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.76: Show issues Location:
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  4. Article ; Online: TK.007: A novel, codon-optimized HSVtk(A168H) mutant for suicide gene therapy.

    Preuss, Ellen / Treschow, Alexandra / Newrzela, Sebastian / Brücher, Daniela / Weber, Kristoffer / Felldin, Ulrika / Alici, Evren / Gahrton, Gösta / von Laer, Dorothee / Dilber, M Sirac / Fehse, Boris

    Human gene therapy

    2010  Volume 21, Issue 8, Page(s) 929–941

    Abstract: Conditional elimination of infused gene-modified alloreactive T cells, using suicide gene activation, has been shown to be an efficient strategy to abrogate severe graft-versus-host disease (GvHD) in the context of adoptive immunotherapy. To overcome ... ...

    Abstract Conditional elimination of infused gene-modified alloreactive T cells, using suicide gene activation, has been shown to be an efficient strategy to abrogate severe graft-versus-host disease (GvHD) in the context of adoptive immunotherapy. To overcome shortcomings of the most widely used suicide gene, wild-type (splice-corrected) herpes simplex virus thymidine kinase (scHSVtk), we generated two new variants: the codon-optimized coHSVtk and, by introducing an additional mutation (A168H), the novel TK.007. We transduced human hematopoietic cell lines and primary T cells with retroviral "sort-suicide vectors" encoding combinations of selection markers (tCD34 and OuaSelect) with one of three HSVtk variants. In vitro we observed higher expression levels and sustained long-term expression of TK.007, indicating lower nonspecific toxicity. Also, we noted significantly improved kinetics of ganciclovir (GCV)-mediated killing for TK.007-transduced cells. In an experimental (murine) allogeneic transplantation model, TK.007-transduced T cells mediated severe GvHD, which was readily abrogated by application of GCV (10 mg/kg). Last, we established a modified allotransplantation model that allowed quantitative comparison of the in vivo activities of TK.007 versus scHSVtk. We found that TK.007 mediates both significantly faster and higher absolute killing at low GCV concentrations (10 and 25 mg/kg). In summary, we demonstrate that the novel TK.007 suicide gene combines better killing performance with reduced nonspecific toxicity (as compared with the frequently used splice-corrected wild-type scHSVtk gene), thus representing a promising alternative for suicide gene therapy.
    MeSH term(s) Animals ; Cell Line ; Codon/genetics ; Codon/metabolism ; Ganciclovir/metabolism ; Genes, Transgenic, Suicide ; Genetic Therapy/methods ; Genetic Vectors ; Graft vs Host Disease/genetics ; Graft vs Host Disease/therapy ; Humans ; Immunotherapy, Adoptive ; Mice ; Mice, Inbred C57BL ; Retroviridae/genetics ; T-Lymphocytes/metabolism ; T-Lymphocytes/virology ; Thymidine Kinase/genetics ; Thymidine Kinase/metabolism ; Transduction, Genetic
    Chemical Substances Codon ; Thymidine Kinase (EC 2.7.1.21) ; Ganciclovir (P9G3CKZ4P5)
    Language English
    Publishing date 2010-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1028152-6
    ISSN 1557-7422 ; 1043-0342
    ISSN (online) 1557-7422
    ISSN 1043-0342
    DOI 10.1089/hum.2009.042
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2988: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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