Targeting of GSK3β promotes imatinib-mediated apoptosis in quiescent CD34 + chronic myeloid leukemia progenitors, preserving normal stem cells

Giovanni Reddiconto, Claudia Toto, Ilaria Palamà, Simone De Leo, Emanuela De Luca, Serena De Matteis, Luciana Dini, Carlo Gambacorti Passerini, Nicola Di Renzo, Michele Maffia, Addolorata Maria Luce Coluccia

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2335-2345
Number of pages11
JournalBlood
Volume119
Issue number10
DOIs
Publication statusPublished - Mar 8 2012

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Reddiconto, G., Toto, C., Palamà, I., De Leo, S., De Luca, E., De Matteis, S., Dini, L., Passerini, C. G., Di Renzo, N., Maffia, M., & Coluccia, A. M. L. (2012). Targeting of GSK3β promotes imatinib-mediated apoptosis in quiescent CD34 + chronic myeloid leukemia progenitors, preserving normal stem cells. Blood, 119(10), 2335-2345. https://doi.org/10.1182/blood-2011-06-361261