NF-κB inhibition triggers death of imatinib-sensitive and imatinib-resistant chronic myeloid leukemia cells including T315I Bcr-Abl mutants

Authors

  • Nadia Lounnas,

    1. INSERM U895/ C3M: Centre Méditerranéen de Médecine Moléculaire, Nice, France
    2. Université Nice Sophia-Antipolis. Faculté de Médecine Pasteur (IFR50), Nice, France
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  • Catherine Frelin,

    1. INSERM U895/ C3M: Centre Méditerranéen de Médecine Moléculaire, Nice, France
    2. Université Nice Sophia-Antipolis. Faculté de Médecine Pasteur (IFR50), Nice, France
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  • Nadège Gonthier,

    1. INSERM U895/ C3M: Centre Méditerranéen de Médecine Moléculaire, Nice, France
    2. Université Nice Sophia-Antipolis. Faculté de Médecine Pasteur (IFR50), Nice, France
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  • Pascal Colosetti,

    1. INSERM U895/ C3M: Centre Méditerranéen de Médecine Moléculaire, Nice, France
    2. Université Nice Sophia-Antipolis. Faculté de Médecine Pasteur (IFR50), Nice, France
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  • Anne Sirvent,

    1. Service d'Hématologie, CHU Archet II, Nice, France
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  • Jil-Patrice Cassuto,

    1. Service d'Hématologie, CHU Archet II, Nice, France
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  • Fréderic Berthier,

    1. DIIM, CHU Cimiez, Nice, France
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  • Nicolas Sirvent,

    1. Service de Pédiatrie, CHU Archet II, Nice, France
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  • Philippe Rousselot,

    1. Service d'Hématologie-Oncologie, Hopital André Mignot, Versailles, France
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  • Michel Dreano,

    1. Merck-Serono International, Geneva, Switzerland
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    • Michel Dreano is an employee of the Merck-Serono International S.A. company, whose IKK2 inhibitor is used in this study.

  • Jean-François Peyron,

    Corresponding author
    1. INSERM U895/ C3M: Centre Méditerranéen de Médecine Moléculaire, Nice, France
    2. Université Nice Sophia-Antipolis. Faculté de Médecine Pasteur (IFR50), Nice, France
    3. Service d'Hématologie, CHU Archet II, Nice, France
    4. Service de Pédiatrie, CHU Archet II, Nice, France
    • INSERM U895, Avenue de Valombrose, 06107 Nice cedex 02, France
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    • Fax: +33-4-93817852.

    • Jean-François Peyron and Véronique Imbert share senior co-authorship.

  • Véronique Imbert

    1. INSERM U895/ C3M: Centre Méditerranéen de Médecine Moléculaire, Nice, France
    2. Université Nice Sophia-Antipolis. Faculté de Médecine Pasteur (IFR50), Nice, France
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    • Jean-François Peyron and Véronique Imbert share senior co-authorship.


Abstract

The Bcr-Abl inhibitor imatinib is the current first-line therapy for all newly diagnosed chronic myeloid leukemia (CML). Nevertheless, resistance to imatinib emerges as CML progresses to an acute deadly phase implying that physiopathologically relevant cellular targets should be validated to develop alternative therapeutic strategies. The NF-κB transcription factor that exerts pro-survival actions is found abnormally active in numerous hematologic malignancies. In the present study, using Bcr-Abl-transfected BaF murine cells, LAMA84 human CML cell line and primary CML, we show that NF-κB is active downstream of Bcr-Abl. Pharmacological blockade of NF-κB by the IKK2 inhibitor AS602868 prevented survival of BaF cells expressing either wild-type, M351T or T315I imatinib-resistant mutant forms of Bcr-Abl both in vitro and in vivo using a mouse xenograft model. AS602868 also affected the survival of LAMA84 cells and of an imatinib-resistant variant. Importantly, the IKK2 inhibitor strongly decreased in vitro survival and ability to form hematopoietic colonies of primary imatinib resistant CML cells including T315I cells. Our data strongly support the targeting of NF-κB as a promising new therapeutic opportunity for the treatment of imatinib resistant CML patients in particular in the case of T315I patients. The T315I mutation escapes all currently used Bcr-Abl inhibitors and is likely to become a major clinical problem as it is associated with a poor clinical outcome. © 2009 UICC

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