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 αVß3 receptor. FAK/Akt pathway activation following integrin ß3 (ITGß3) 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.