title: Effect of tyrosine kinase inhibitors on stemness in normal and chronic myeloid leukemia cells.
abstract: Although tyrosine kinase inhibitors (TKIs) efficiently cure chronic myeloid leukemia (CML), they can fail to eradicate CML stem cells (CML-SCs). The mechanisms responsible for CML-SC survival need to be understood for designing therapies. Several previous studies suggest that TKIs could modulate CML-SC quiescence. Unfortunately, CML-SCs are insufficiently available. Induced pluripotent stem cells (iPSCs) offer a promising alternative. In this work, we used iPSCs derived from CML patients (Ph+). Ph+ iPSC clones expressed lower levels of stemness markers than normal iPSCs. BCR-ABL1 was found to be involved in stemness regulation and ERK1/2 to have a key role in the signaling pathway. TKIs unexpectedly promoted stemness marker expression in Ph+ iPSC clones. Imatinib also retained quiescence and induced stemness gene expression in CML-SCs. Our results suggest that TKIs might have a role in residual disease and confirm the need for a targeted therapy different from TKIs that could overcome the stemness-promoting effect caused by TKIs. Interestingly, a similar pro-stemness effect was observed in normal iPSCs and hematopoietic SCs. These findings could help to explain CML resistance mechanisms and the teratogenic side-effects of TKIs in embryonic cells.
authors.affiliation: Inserm U1035, Biothérapies des Maladies Génétiques et Cancers, Bordeaux, France.|Université de Bordeaux, FR TransBiomed, Bordeaux, France.|Laboratoire d'Excellence GR-Ex, Bordeaux, France.
authors.forename: L
authors.initials: L
authors.lastname: Charaf
authors.affiliation: Inserm U1035, Biothérapies des Maladies Génétiques et Cancers, Bordeaux, France.|Université de Bordeaux, FR TransBiomed, Bordeaux, France.|Pôle de Biologie et Pathologie CHU Bordeaux, Bordeaux, France.|Institut Bergonie, SIRIC BRIO, Bordeaux, France.
authors.forename: F-X
authors.initials: FX
authors.lastname: Mahon
authors.affiliation: Inserm U1035, Biothérapies des Maladies Génétiques et Cancers, Bordeaux, France.|Université de Bordeaux, FR TransBiomed, Bordeaux, France.|Laboratoire d'Excellence GR-Ex, Bordeaux, France.
authors.forename: I
authors.initials: I
authors.lastname: Lamrissi-Garcia
authors.affiliation: Inserm U1035, Biothérapies des Maladies Génétiques et Cancers, Bordeaux, France.|Université de Bordeaux, FR TransBiomed, Bordeaux, France.|Laboratoire d'Excellence GR-Ex, Bordeaux, France.
authors.forename: I
authors.initials: I
authors.lastname: Moranvillier
authors.affiliation: Inserm U1035, Biothérapies des Maladies Génétiques et Cancers, Bordeaux, France.|Laboratoire d'Excellence GR-Ex, Bordeaux, France.
authors.forename: F
authors.initials: F
authors.lastname: Beliveau
authors.affiliation: Inserm U1035, Biothérapies des Maladies Génétiques et Cancers, Bordeaux, France.|Université de Bordeaux, FR TransBiomed, Bordeaux, France.|Institut Polytechnique de Bordeaux, Talence, France.
authors.forename: B
authors.initials: B
authors.lastname: Cardinaud
authors.affiliation: Inserm U1035, Biothérapies des Maladies Génétiques et Cancers, Bordeaux, France.|Université de Bordeaux, FR TransBiomed, Bordeaux, France.|Laboratoire d'Excellence GR-Ex, Bordeaux, France.|Pôle de Biologie et Pathologie CHU Bordeaux, Bordeaux, France.
authors.forename: S
authors.initials: S
authors.lastname: Dabernat
authors.affiliation: Inserm U1035, Biothérapies des Maladies Génétiques et Cancers, Bordeaux, France.|Université de Bordeaux, FR TransBiomed, Bordeaux, France.|Laboratoire d'Excellence GR-Ex, Bordeaux, France.|Pôle de Biologie et Pathologie CHU Bordeaux, Bordeaux, France.
authors.forename: H
authors.initials: H
authors.lastname: de Verneuil
authors.affiliation: Inserm U1035, Biothérapies des Maladies Génétiques et Cancers, Bordeaux, France.|Université de Bordeaux, FR TransBiomed, Bordeaux, France.|Laboratoire d'Excellence GR-Ex, Bordeaux, France.|Pôle de Biologie et Pathologie CHU Bordeaux, Bordeaux, France.
authors.forename: F
authors.initials: F
authors.lastname: Moreau-Gaudry
authors.affiliation: Inserm U1035, Biothérapies des Maladies Génétiques et Cancers, Bordeaux, France.|Université de Bordeaux, FR TransBiomed, Bordeaux, France.|Laboratoire d'Excellence GR-Ex, Bordeaux, France.|Pôle de Biologie et Pathologie CHU Bordeaux, Bordeaux, France.
authors.forename: A
authors.initials: A
authors.lastname: Bedel
mesh_terms: D016044:Fusion Proteins, bcr-abl / Q000502:physiology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000473:pathology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl