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Chronic Myeloproliferative Neoplasias

The stem cell factor–c-KIT pathway must be inhibited to enable apoptosis induced by BCR–ABL inhibitors in chronic myelogenous leukemia cells

Leukemia volume 23, pages 679–685 (2009)Cite this article

Abstract

Imatinib is an effective first-line therapy for chronic myelogenous leukemia (CML) that acts by targeting the tyrosine kinase activity of BCR–ABL. To overcome resistance, second-generation inhibitors of BCR–ABL have been developed. Among these, nilotinib is more potent against BCR–ABL than imatinib, and is effective against many imatinib-resistant BCR–ABL mutants. In this study, an in vitro flow cytometry assay to analyze imatinib- and nilotinib-induced apoptosis in CML cells has been developed. Both the drugs induced significant apoptosis in CD34+ cells from 36 CML bone marrow samples (P<10−4), whereas CD34+ cells from BCR–ABL negative samples were unaffected. When the experiments were carried out in the presence of a cocktail of cytokines, nilotinib- but not imatinib-induced apoptosis was inhibited. This differential inhibition was confirmed on K562 cells. A blocking anti-CD117 antibody alleviated the antiapoptotic effect of cytokines against nilotinib. Moreover, using short hairpin RNA against BCR–ABL, we showed that K562 cells were not dependent on BCR–ABL signaling as long as the stem cell factor (SCF) receptor pathway was activated. We conclude that the c-KIT pathway may substitute for BCR–ABL tyrosine kinase to activate survival signals, and that c-KIT must be inhibited besides Bcr–Abl to allow apoptosis of CML cells.

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Acknowledgements

This study was supported by grants from the Comité de Gironde de la Ligue Nationale contre le Cancer and the Fondation Laurette Fugain.

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Authors and Affiliations

  1. Laboratoire d'hématopoïèse leucémique et cibles thérapeutiques, INSERM U876, Université Victor Ségalen, Bordeaux cedex, France

    F Belloc, K Airiau, M Jeanneteau, M Garcia, E Guérin, E Lippert & F-X Mahon

  2. Laboratoire d'Hématologie, Hôpital du Haut Lévèque, CHU Bordeaux, Pessac, France

    F Belloc, K Airiau, E Guérin, E Lippert, F Moreau-Gaudry & F-X Mahon

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  1. F Belloc
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Correspondence to F Belloc.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Belloc, F., Airiau, K., Jeanneteau, M. et al. The stem cell factor–c-KIT pathway must be inhibited to enable apoptosis induced by BCR–ABL inhibitors in chronic myelogenous leukemia cells. Leukemia 23, 679–685 (2009). https://doi.org/10.1038/leu.2008.364

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