TY - JOUR
T1 - Targeting of GSK3β promotes imatinib-mediated apoptosis in quiescent CD34 + chronic myeloid leukemia progenitors, preserving normal stem cells
AU - Reddiconto, Giovanni
AU - Toto, Claudia
AU - Palamà, Ilaria
AU - De Leo, Simone
AU - De Luca, Emanuela
AU - De Matteis, Serena
AU - Dini, Luciana
AU - Passerini, Carlo Gambacorti
AU - Di Renzo, Nicola
AU - Maffia, Michele
AU - Coluccia, Addolorata Maria Luce
PY - 2012/3/8
Y1 - 2012/3/8
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2011-06-361261
DO - 10.1182/blood-2011-06-361261
M3 - Article
C2 - 22262776
AN - SCOPUS:84858032395
VL - 119
SP - 2335
EP - 2345
JO - Blood
JF - Blood
SN - 0006-4971
IS - 10
ER -