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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, CD34 / metabolism
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Apoptosis / drug effects*
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Benzamides
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Blotting, Western
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Cell Nucleus / metabolism
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Cells, Cultured
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Cyclin D1 / metabolism
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Cytokines / pharmacology
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Dasatinib
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Drug Synergism
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Fusion Proteins, bcr-abl / antagonists & inhibitors
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / metabolism
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Hematopoietic Stem Cells / drug effects*
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Hematopoietic Stem Cells / metabolism
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Humans
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Imatinib Mesylate
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Indoles / pharmacology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Maleimides / pharmacology
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Microscopy, Confocal
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Mitogen-Activated Protein Kinases / metabolism
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Phosphorylation / drug effects
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Piperazines / pharmacology*
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Protein Kinase Inhibitors / pharmacology
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Protein Transport / drug effects
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Proto-Oncogene Proteins pp60(c-src) / metabolism
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Pyrimidines / pharmacology*
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Signal Transduction / drug effects
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Thiazoles / pharmacology
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beta Catenin / metabolism
Substances
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Antigens, CD34
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Benzamides
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Cytokines
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Indoles
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Maleimides
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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SB 216763
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Thiazoles
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beta Catenin
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Cyclin D1
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Imatinib Mesylate
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Fusion Proteins, bcr-abl
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Proto-Oncogene Proteins pp60(c-src)
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Mitogen-Activated Protein Kinases
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Glycogen Synthase Kinase 3
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Dasatinib