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Apoptosis

Inhibition of imatinib-mediated apoptosis by the caspase-cleaved form of the tyrosine kinase Lyn in chronic myelogenous leukemia cells

Leukemia volume 23, pages 1500–1506 (2009)Cite this article

Abstract

Once cleaved by caspases, the Lyn tyrosine kinase (LynΔN) is relocalized from the plasma membrane to the cytoplasm of apoptotic cells, but the function of such a cleavage is incompletely understood. We evaluated the effect of LynΔN overexpression on imatinib sensitivity of the chronic myelogenous leukemia (CML) cell line K562. Therefore, we generated stable cells that express plasmids encoding LynΔN or its catalytically inactive counterpart LynΔNKD. We established that Lyn is cleaved in imatinib-treated parental K562 cells in a caspase-dependent manner. Lyn cleavage also occurred following BCR-ABL silencing by specific short hairpin RNA (sh-RNA). Imatinib-induced apoptosis was abrogated in LynΔN-overexpressing cells, but not in cells overexpressing its inactive counterpart. Conversely, the overexpression of LynΔN failed to affect the differentiation of K562 cells. Importantly, the protective effect of LynΔN was suppressed by two inhibitors of Lyn activity. LynΔN also inhibits imatinib-mediated caspase-3 activation in the small proportion of nilotinib-resistant K562 cells overexpressing Lyn that can engage an apoptotic program upon imatinib stimulation. Finally, Lyn knockdown by sh-RNA altered neither imatinib-mediated apoptosis nor differentiation. Taken together, our data show that the caspase-cleaved form of Lyn exerts a negative feedback on imatinib-mediated CML cell apoptosis that is entirely dependent on its kinase activity and likely on the BCR–ABL pathway.

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Acknowledgements

We are indebted to Pr E Van-Obberghen (INSERM U907, Nice, France) for reviewing this manuscript. This work was supported by INSERM, l’Institut National du Cancer (INCA grant PL-06-26), and the Fondation de France. SM is a post-doctoral fellow of the Fondation de France.

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Author notes

  1. P Gamas and S Marchetti: These authors contributed equally to this work.

Authors and Affiliations

  1. Team 2: Cell Death Differentiation and Cancer, INSERM U895, Nice, France

    P Gamas, S Marchetti, A Puissant, S Grosso, P Colosetti & P Auberger

  2. Université de Nice-Sophia-Antipolis, UFR Médecine, Nice, France

    P Gamas, S Marchetti, A Puissant, S Grosso, P Colosetti & P Auberger

  3. Equipe Labellisée par la Ligue Nationale Contre le Cancer, Paris, France

    A Puissant, S Grosso, P Colosetti & P Auberger

  4. Faculty of Medicine, INSERM U866, Dijon, France

    A Jacquel

  5. INSERM U876, Université Victor Segalen-2, Bordeaux, France

    J-M Pasquet & F-X Mahon

  6. Centre Hospitalier Universitaire de Nice, Hôpital de l’Archet, Service d’Hématologie Clinique, Nice, France

    J-P Cassuto & P Auberger

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Gamas, P., Marchetti, S., Puissant, A. et al. Inhibition of imatinib-mediated apoptosis by the caspase-cleaved form of the tyrosine kinase Lyn in chronic myelogenous leukemia cells. Leukemia 23, 1500–1506 (2009). https://doi.org/10.1038/leu.2009.60

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