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Imatinib triggers mesenchymal-like conversion of CML cells associated with increased aggressiveness.

Abstract : Chronic myelogenous leukemia (CML) is a cytogenetic disorder resulting from the expression of p210BCR-ABL. Imatinib, an inhibitor of BCR-ABL, has emerged as the leading compound to treat CML patients. Despite encouraging clinical results, resistance to imatinib represents a major drawback for therapy, as a substantial proportion of patients are refractory to this treatment. Recent publications have described the existence of a small cancer cell population with the potential to exhibit the phenotypic switch responsible for chemoresistance. To investigate the existence of such a chemoresistant cellular subpopulation in CML, we used a two-step approach of pulse and continuous selection by imatinib in different CML cell lines that allowed the emergence of a subpopulation of adherent cells (IM-R Adh) displaying an epithelial-mesenchymal transition (EMT)-like phenotype. Overexpression of several EMT markers was observed in this CML subpopulation, as well as in CD34(+) CML primary cells from patients who responded poorly to imatinib treatment. In response to imatinib, this CD44(high)/CD24(low) IM-R Adh subpopulation exhibited increased adhesion, transmigration and invasion in vitro and in vivo through specific overexpression of the αVβ3 receptor. FAK/Akt pathway activation following integrin β3 (ITGβ3) engagement mediated the migration and invasion of IM-R Adh cells, whereas persistent activation of ERK counteracted BCR-ABL inhibition by imatinib, promoting cell adhesion-mediated resistance.
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Contributor : Caroline Ruiz <>
Submitted on : Tuesday, January 8, 2013 - 11:00:36 AM
Last modification on : Monday, October 12, 2020 - 10:28:15 AM

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Alexandre Puissant, Maeva Dufies, Nina Fenouille, Issam Ben Sahra, Arnaud Jacquel, et al.. Imatinib triggers mesenchymal-like conversion of CML cells associated with increased aggressiveness.. Journal of molecular cell biology, Oxford UP, 2012, 4 (4), pp.207-20. ⟨10.1093/jmcb/mjs010⟩. ⟨hal-00771201⟩



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