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

Alexandre Puissant, Maeva Dufies, Nina Fenouille, Issam Ben Sahra, Arnaud Jacquel, Guillaume Robert, Thomas Cluzeau, Marcel Deckert, Mélanie Tichet, Yann Chéli, Jill Patrice Cassuto, Sophie Raynaud, Laurence Legros, Jean Max Pasquet, François Xavier Mahon, Frédéric Luciano, Patrick Auberger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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 epithelialmesenchymal 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/CD24low 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.

Original languageEnglish (US)
Pages (from-to)207-220
Number of pages14
JournalJournal of molecular cell biology
Volume4
Issue number4
DOIs
StatePublished - Aug 2012

Keywords

  • CD44/CD24 subpopulation
  • ITGB3
  • cell adhesion-mediated drug resistance (CAM-DR)
  • chronic myelogenous leukemia
  • imatinib resistance

ASJC Scopus subject areas

  • Medicine(all)

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