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Apoptosis and erythroid differentiation triggered by Bcr-Abl inhibitors in CML cell lines are fully distinguishable processes that exhibit different sensitivity to caspase inhibition

Oncogene volume 26, pages 2445–2458 (2007)Cite this article

Abstract

Imatinib targets the Bcr-Abl oncogene that causes chronic myelogenous leukemia (CML) in humans. Recently, we demonstrated that besides triggering apoptosis in K562 cells, imatinib also mediated their erythroid differentiation. Although both events appear to proceed concomitantly, it is not known at present whether or not imatinib-induced apoptosis and differentiation are interdependent processes. Hence, we investigated the requirements for Bcr-Abl inhibitor-mediated apoptosis and erythroid differentiation in several established and engineered CML cell lines. Imatinib triggered apoptosis and erythroid differentiation of different CML cell lines, but only apoptosis exhibited sensitivity to ZVAD-fmk inhibition. Conversely, the p38 mitogen-activated protein (MAP) kinase inhibitor, SB202190, significantly slowed down erythroid differentiation without affecting caspase activation. Furthermore, imatinib and PD166326, another Bcr-Abl inhibitory molecule, triggered erythroid differentiation of K562 cell clones, nevertheless resistant to Bcr-Abl inhibitor-induced apoptosis. Finally, short hairpin RNA inhibitor (shRNAi) silencing of caspase 3 efficiently inhibited caspase activity but had no effect on erythroid differentiation, whereas silencing of Bcr-Abl mimicked imatinib or PD166326 treatment, leading to increased apoptosis and erythroid differentiation of K562 cells. Taken together, our findings not only demonstrate that Bcr-Abl inhibitor-mediated apoptosis and differentiation are fully distinguishable events, but also that caspases are dispensable for erythroid differentiation of established CML cell lines.

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Acknowledgements

We are indebted to Dr Hans Clever for the kind gift of the pTER vector for inducible expression of shRNAi. We thank Novartis for the kind gift of imatinib mesylate and Pfizer for that of PD166326. SM and AJ are recipients of fellowships from the Fondation contre la Leucémie and the Ligue Nationale contre le Cancer, respectively.

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Authors and Affiliations

  1. INSERM, U526, Cell Death Differentiation and Cancer Team, Equipe labellisée par la Ligue Nationale contre le Cancer, Nice, France

    A Jacquel, P Colosetti, S Grosso, N Belhacene, A Puissant, S Marchetti & P Auberger

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

    A Jacquel, P Colosetti, S Grosso, N Belhacene, A Puissant, S Marchetti, J-P Breittmayer & P Auberger

  3. INSERM, U576, CHU de Nice, Hôpital de l'Archet, Nice, France

    J-P Breittmayer

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  1. A Jacquel
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Correspondence to P Auberger.

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Jacquel, A., Colosetti, P., Grosso, S. et al. Apoptosis and erythroid differentiation triggered by Bcr-Abl inhibitors in CML cell lines are fully distinguishable processes that exhibit different sensitivity to caspase inhibition. Oncogene 26, 2445–2458 (2007). https://doi.org/10.1038/sj.onc.1210034

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