title: Targeting of GSK3β promotes imatinib-mediated apoptosis in quiescent CD34+ chronic myeloid leukemia progenitors, preserving normal stem cells.
abstract: The targeting of BCR-ABL, a hybrid oncogenic tyrosine (Y) kinase, does not eradicate chronic myeloid leukemia (CML)-initiating cells. Activation of β-catenin was linked to CML leukemogenesis and drug resistance through its BCR-ABL-dependent Y phosphorylation and impaired binding to GSK3β (glycogen synthase kinase 3β). Herein, we show that GSK3β is constitutively Y(216) phospho-activated and predominantly relocated to the cytoplasm in primary CML stem/progenitor cells compared with its balanced active/inactive levels and cytosolic/nuclear distribution in normal cells. Under cytokine support, persistent GSK3β activity and its altered subcellular localization were correlated with BCR-ABL-dependent and -independent activation of MAPK and p60-SRC/GSK3β complex formation. Specifically, GSK3β activity and nuclear import were increased by imatinib mesylate (IM), a selective ABL inhibitor, but prevented by dasatinib that targets both BCR-ABL- and cytokine-dependent MAPK/p60-SRC activity. SB216763, a specific GSK3 inhibitor, promoted an almost complete suppression of primary CML stem/progenitor cells when combined with IM, but not dasatinib, while sparing bcr-abl-negative cells. Our data indicate that GSK3 inhibition acts to prime a pro-differentiative/apoptotic transcription program in the nucleus of IM-treated CML cells by affecting the β-catenin, cyclinD1, C-EBPα, ATF5, mTOR, and p27 levels. In conclusion, our data gain new insight in CML biology, indicating that GSK3 inhibitors may be of therapeutic value in selectively targeting leukemia-initiating cells in combination with IM but not dasatinib.
authors.affiliation: Hematology Unit, Vito Fazzi Hospital Azienda Sanitaria Locale Leece, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Reddiconto
authors.forename: Claudia
authors.initials: C
authors.lastname: Toto
authors.forename: Ilaria
authors.initials: I
authors.lastname: Palamà
authors.forename: Simone
authors.initials: S
authors.lastname: De Leo
authors.forename: Emanuela
authors.initials: E
authors.lastname: de Luca
authors.forename: Serena
authors.initials: S
authors.lastname: De Matteis
authors.forename: Luciana
authors.initials: L
authors.lastname: Dini
authors.forename: Carlo Gambacorti
authors.initials: CG
authors.lastname: Passerini
authors.forename: Nicola
authors.initials: N
authors.lastname: Di Renzo
authors.forename: Michele
authors.initials: M
authors.lastname: Maffia
authors.forename: Addolorata Maria Luce
authors.initials: AM
authors.lastname: Coluccia
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D000069439:Dasatinib; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008301:Maleimides / Q000494:pharmacology; D018613:Microscopy, Confocal; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D001549:Benzamides; D016207:Cytokines; D007211:Indoles; D008301:Maleimides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C417521:SB 216763; D013844:Thiazoles; D051176:beta Catenin; D019938:Cyclin D1; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D016392:Proto-Oncogene Proteins pp60(c-src); C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D000069439:Dasatinib