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Chronic Myeloproliferative Neoplasias

Cathepsin B release after imatinib-mediated lysosomal membrane permeabilization triggers BCR–ABL cleavage and elimination of chronic myelogenous leukemia cells

Leukemia volume 24, pages 115–124 (2010)Cite this article

Abstract

Imatinib is the leading compound to treat patients with chronic myelogenous leukemia (CML) but the exact mechanism of its anti-leukemic effect is incompletely elucidated. Through inhibition of BCR–ABL, Imatinib blocks several downstream pathways and induces apoptosis of BCR–ABL positive cells. In this study, we analyzed further the mode of action of Imatinib in different appropriate cellular models of CML either sensitive or resistant to Imatinib and in CD34+ cells from CML patients. Pharmacological or short hairpin RNA-mediated inhibition of BCR–ABL triggers lysosomal membrane permeabilization (LMP) that culminates in activation and redistribution of Cathepsin B (CB) into the cytoplasm of CML cells, in which it triggers directly BCR–ABL degradation. Pharmacological inhibition of CB by CA-074Me or small interfering RNA-mediated knock-down of CB partly protects K562 cells from Imatinib-induced cell death and CB overexpression sensitizes these cells to Imatinib killing. Strikingly, Imatinib-triggered LMP, CB activation and BCR–ABL cleavage in CD34+ cells from CML patients and inhibition of CB confers protection against cell death in clonogenic assays of CD34+ primary cells from CML patients. Hence, we describe an original pathway by which Imatinib participates to the elimination of CML cells through LMP and CB-mediated specific degradation of BCR–ABL.

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Acknowledgements

We are indebted to clinician colleagues from CHU and Centre Antoine Lacassagne of Nice, and Centre Hospitalier Princesse Grace of Monaco, for their generosity in providing patient samples. We also thank the patients enrolled in this study. We thank Dr H Clevers, at the Hubrecht Laboratory, Utrecht, The Netherlands for the pTer plasmid for inducible shRNA expression. We are indebted to Professor JV Melo at the Imperial College of London, UK and Professor FX Mahon, INSERM U876 Bordeaux, France for the kind gift of parental Baf/3 cells and Baf/3 cells carrying the T315I mutation. This work was also supported by The Institute National des Canceropoles (INCA 2006 PL-026). GR is the recipient from an INCA fellowship.

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Authors and Affiliations

  1. INSERM 895, Team 2 Cell Death Differentiation and Cancer, Nice, France

    A Puissant, P Colosetti, G Robert & P Auberger

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

    A Puissant, P Colosetti, G Robert & P Auberger

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

    A Puissant, P Colosetti, G Robert & P Auberger

  4. Centre Hospitalier Universitaire de Nice, Hopital de l'Archet, Service d'Hématologie Clinique, Nice, France

    J-P Cassuto & P Auberger

  5. Centre Hospitalier Universitaire de Nice, Hopital Pasteur, Laboratoire d'Oncohématologie, Nice, France

    S Raynaud

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  1. A Puissant
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Correspondence to P Auberger.

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

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Puissant, A., Colosetti, P., Robert, G. et al. Cathepsin B release after imatinib-mediated lysosomal membrane permeabilization triggers BCR–ABL cleavage and elimination of chronic myelogenous leukemia cells. Leukemia 24, 115–124 (2010). https://doi.org/10.1038/leu.2009.233

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