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    BIM mediates synergistic killing of B-cell acute lymphoblastic leukemia cells by BCL-2 and MEK inhibitors.

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    Authors
    Korfi, Koorosh
    Smith, Matthew
    Swan, Jacqueline
    Somervaille, Tim C P
    Dhomen, Nathalie
    Marais, Richard
    Affiliation
    Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester
    Issue Date
    2016
    
    Metadata
    Show full item record
    Abstract
    B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological disease that kills ~50% of adult patients. With the exception of some BCR-ABL1(+) patients who benefit from tyrosine kinase inhibitors, there are no effective targeted therapies for adult B-ALL patients and chemotherapy remains first-line therapy despite adverse side effects and poor efficacy. We show that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition does not suppress B-ALL cell growth. However, MEK inhibition synergized with BCL-2/BCL-XL family inhibitors to suppress proliferation and induce apoptosis in B-ALL cells. We show that this synergism is mediated by the pro-apoptotic factor BIM, which is dephosphorylated as a result of MEK inhibition, allowing it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death. This cooperative effect is observed in B-ALL cells driven by a range of genetic abnormalities and therefore has significant therapeutic potential.
    Citation
    BIM mediates synergistic killing of B-cell acute lymphoblastic leukemia cells by BCL-2 and MEK inhibitors. 2016, 7:e2177 Cell Death Dis
    Journal
    Cell Death & Disease
    URI
    http://hdl.handle.net/10541/606632
    DOI
    10.1038/cddis.2016.70
    PubMed ID
    27054332
    Type
    Article
    Language
    en
    ISSN
    2041-4889
    ae974a485f413a2113503eed53cd6c53
    10.1038/cddis.2016.70
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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