Targeting of GSK3 beta promotes imatinib-mediated apoptosis in quiescent CD34(+) chronic myeloid leukemia progenitors, preserving normal stem cells

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Abstract

The targeting of BCR-ABL, a hybrid oncogenic tyrosine (Y) kinase, does not eradicate chronic myeloid leukemia (CML)-initiating cells. Activation of beta-catenin was linked to CML leukemogenesis and drug resistance through its BCR-ABL-dependent Y phosphorylation and impaired binding to GSK3 beta (glycogen synthase kinase 3 beta). Herein, we show that GSK3 beta 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 GSK3 beta activity and its altered subcellular localization were correlated with BCR-ABL-dependent and -independent activation of MAPK and p60-SRC/GSK3 beta complex formation. Specifically, GSK3 beta 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 beta-catenin, cyclinD1, C-EBP alpha, 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. (Blood. 2012;119(10):2335-2345)

Autore Pugliese

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  • Reddiconto G.; Toto C.; Palama I.; De Leo S.; de Luca E.; De Matteis S.; Dini L.; Passerini C.G.; Di Renzo N.; Maffia M.; Coluccia A.M.L.

Titolo volume/Rivista

Blood

Anno di pubblicazione

2012

ISSN

0006-4971

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