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  1. Article ; Online: mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia.

    Malik, Natasha / Hay, Jodie / Almuhanna, Hassan N B / Dunn, Karen M / Lees, Jamie / Cassels, Jennifer / Li, Jiatian / Nakagawa, Rinako / Sansom, Owen J / Michie, Alison M

    Leukemia

    2023  Volume 37, Issue 12, Page(s) 2414–2425

    Abstract: Targeted deletion of Raptor, a component of mechanistic target of rapamycin complex 1 (mTORC1), reveals an essential role for mTORC1 in initiation/maintenance of leukemia in a CLL model, resulting from a failure for haemopoietic stem/progenitor cells ( ... ...

    Abstract Targeted deletion of Raptor, a component of mechanistic target of rapamycin complex 1 (mTORC1), reveals an essential role for mTORC1 in initiation/maintenance of leukemia in a CLL model, resulting from a failure for haemopoietic stem/progenitor cells (HSPCs) to commit to the B cell lineage. Induction of Raptor-deficiency in NSG mice transplanted with Mx1-Raptor CLL progenitor cells (PKCα-KR-transduced HSPCs) after disease establishment revealed a reduction in CLL-like disease load and a significant increase in survival in the mice. Interestingly in an aggressive CLL-like disease model, rapamycin treatment reduced disease burden more effectively than AZD2014 (dual mTORC1/2 inhibitor), indicating a skew towards mTORC1 sensitivity with more aggressive disease. Rapamycin, but not ibrutinib, efficiently targeted the eEF2/eEF2K translation elongation regulatory axis, downstream of mTORC1, resulting in eEF2 inactivation through induction of eEF2
    MeSH term(s) Humans ; Animals ; Mice ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Signal Transduction ; Sirolimus ; Phosphorylation ; Disease Progression
    Chemical Substances Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Sirolimus (W36ZG6FT64)
    Language English
    Publishing date 2023-09-29
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 807030-1
    ISSN 1476-5551 ; 0887-6924
    ISSN (online) 1476-5551
    ISSN 0887-6924
    DOI 10.1038/s41375-023-02043-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2295: Show issues Location:
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  2. Article ; Online: mTORC1 activity is essential for erythropoiesis and B cell lineage commitment.

    Malik, Natasha / Dunn, Karen M / Cassels, Jennifer / Hay, Jodie / Estell, Christopher / Sansom, Owen J / Michie, Alison M

    Scientific reports

    2019  Volume 9, Issue 1, Page(s) 16917

    Abstract: Mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that mediates phosphoinositide-3-kinase (PI3K)/AKT signalling. This pathway is involved in a plethora of cellular functions including protein and lipid synthesis, cell migration, ...

    Abstract Mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that mediates phosphoinositide-3-kinase (PI3K)/AKT signalling. This pathway is involved in a plethora of cellular functions including protein and lipid synthesis, cell migration, cell proliferation and apoptosis. In this study, we proposed to delineate the role of mTORC1 in haemopoietic lineage commitment using knock out (KO) mouse and cell line models. Mx1-cre and Vav-cre expression systems were used to specifically target Raptor
    MeSH term(s) Animals ; B-Lymphocytes/cytology ; B-Lymphocytes/metabolism ; Biomarkers ; Cell Differentiation ; Cell Line, Tumor ; Cell Lineage ; Erythropoiesis ; Humans ; Lymphopoiesis ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice ; Mice, Knockout ; Models, Biological ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction
    Chemical Substances Biomarkers ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
    Language English
    Publishing date 2019-11-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-019-53141-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling.

    Hay, Jodie / Tarafdar, Anuradha / Holroyd, Ailsa K / Moka, Hothri A / Dunn, Karen M / Alshayeb, Alzahra / Lloyd, Bryony H / Cassels, Jennifer / Malik, Natasha / Khan, Ashfia F / Sou, IengFong / Lees, Jamie / Almuhanna, Hassan N B / Kalakonda, Nagesh / Slupsky, Joseph R / Michie, Alison M

    Cancers

    2022  Volume 14, Issue 23

    Abstract: B cell antigen receptor (BCR) signalling competence is critical for the pathogenesis of chronic lymphocytic leukaemia (CLL). Defining key proteins that facilitate these networks aid in the identification of targets for therapeutic exploitation. We ... ...

    Abstract B cell antigen receptor (BCR) signalling competence is critical for the pathogenesis of chronic lymphocytic leukaemia (CLL). Defining key proteins that facilitate these networks aid in the identification of targets for therapeutic exploitation. We previously demonstrated that reduced PKCα function in mouse hematopoietic stem/progenitor cells (HPSCs) resulted in PKCβII upregulation and generation of a poor-prognostic CLL-like disease. Here,
    Language English
    Publishing date 2022-12-06
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers14236006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: AKT/mTORC2 Inhibition Activates FOXO1 Function in CLL Cells Reducing B-Cell Receptor-Mediated Survival.

    Cosimo, Emilio / Tarafdar, Anuradha / Moles, Michael W / Holroyd, Ailsa K / Malik, Natasha / Catherwood, Mark A / Hay, Jodie / Dunn, Karen M / Macdonald, Alan M / Guichard, Sylvie M / O'Rourke, Declan / Leach, Michael T / Sansom, Owen J / Cosulich, Sabina C / McCaig, Alison M / Michie, Alison M

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2018  Volume 25, Issue 5, Page(s) 1574–1587

    Abstract: Purpose: To determine whether inhibition of mTOR kinase-mediated signaling represents a valid therapeutic approach for chronic lymphocytic leukemia (CLL).: Experimental design: Stratification of mTOR activity was carried out in patients with primary ... ...

    Abstract Purpose: To determine whether inhibition of mTOR kinase-mediated signaling represents a valid therapeutic approach for chronic lymphocytic leukemia (CLL).
    Experimental design: Stratification of mTOR activity was carried out in patients with primary CLL samples and an aggressive CLL-like mouse model. The potency of dual mTOR inhibitor AZD8055 to induce apoptosis in primary CLL cells was assessed in the presence/absence of B-cell receptor (BCR) ligation. Furthermore, we addressed the molecular and functional impact of dual mTOR inhibition in combination with BTK inhibitor ibrutinib.
    Results: Differential regulation of basal mTORC1 activity was observed in poor prognostic CLL samples, with elevated p4EBP1
    Conclusions: Our studies demonstrate that dual mTOR inhibitors show promise as future CLL therapies, particularly in combination with ibrutinib.
    MeSH term(s) Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Disease Models, Animal ; Drug Synergism ; Female ; Forkhead Box Protein O1/genetics ; Forkhead Box Protein O1/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell/mortality ; Male ; Mechanistic Target of Rapamycin Complex 2/antagonists & inhibitors ; Mechanistic Target of Rapamycin Complex 2/metabolism ; Mice ; Mice, Transgenic ; Prognosis ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt/metabolism ; Receptors, Antigen, B-Cell/metabolism ; Signal Transduction/drug effects ; Treatment Outcome ; Xenograft Model Antitumor Assays
    Chemical Substances FOXO1 protein, human ; Forkhead Box Protein O1 ; Protein Kinase Inhibitors ; Receptors, Antigen, B-Cell ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
    Language English
    Publishing date 2018-12-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-18-2036
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4223: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    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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