title: 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.
authors.affiliation: INSERM U1065, Team: Cell Death, Differentiation, Inflammation and Cancer, Nice, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Puissant
authors.forename: Maeva
authors.initials: M
authors.lastname: Dufies
authors.forename: Nina
authors.initials: N
authors.lastname: Fenouille
authors.forename: Issam
authors.initials: I
authors.lastname: Ben Sahra
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jacquel
authors.forename: Guillaume
authors.initials: G
authors.lastname: Robert
authors.forename: Thomas
authors.initials: T
authors.lastname: Cluzeau
authors.forename: Marcel
authors.initials: M
authors.lastname: Deckert
authors.forename: Mélanie
authors.initials: M
authors.lastname: Tichet
authors.forename: Yann
authors.initials: Y
authors.lastname: Chéli
authors.forename: Jill-Patrice
authors.initials: JP
authors.lastname: Cassuto
authors.forename: Sophie
authors.initials: S
authors.lastname: Raynaud
authors.forename: Laurence
authors.initials: L
authors.lastname: Legros
authors.forename: Jean-Max
authors.initials: JM
authors.lastname: Pasquet
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Mahon
authors.forename: Frédéric
authors.initials: F
authors.lastname: Luciano
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D008648:Mesoderm / Q000187:drug effects* / Q000473:pathology*; D051379:Mice; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D039302:Integrin alphaVbeta3; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate