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 ␤-catenin was linked to CML leukemogenesis and drug resistance through its BCR-ABLdependent Y phosphorylation and impaired binding to GSK3␤ (glycogen synthase kinase 3␤). Herein, we show that GSK3␤ is constitutively Y 216 phosphoactivated 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␤ activity and its altered subcellular localization were correlated with BCR-ABL-dependent and -independent activation of MAPK and p60-SRC/GSK3␤ complex formation. Specifically, GSK3␤ 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 ␤-catenin, cyclinD1, C-EBP␣, 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.

Biological basis and clinical study of glycogen synthase kinase- 3β-targeted therapy by drug repositioning for glioblastoma

“…Aberrant regulation of pGSK3β Y216 could promote the malignant features of GBM [18, 19, 35] since it is an independent prognostic factor for GBM patient in the present study. Elevated pGSK3β Y216 fraction contributed the malignant feature of pancreatic cancer [36] and inhibition of pGSK3β Y216 enhanced the effect of imatinib inducing apoptosis in chronic myeloid leukemia [35]. These knowledge and observations support the present study showing that lithium and valproate inhibiting pGSK3β Y216 exhibited stronger antitumoral effect than cimetidine and olanzapine that induce pGSK3β S9 .…”

Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention

“…128 GSK-3β is constitutively phosphorylated on Y216 and predominantly localized in the cytoplasm in CML stem/progenitor cells that contrasts with the cytoplasmic/nuclear localization and activation status of GSK-3β in normal cells. BCR-ABL can regulate the activation of the Raf/MEK/ERK pathway and Src/GSK-3β.…”

Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond

“…140 Interestingly, although GSK-3β negatively regulates β-catenin, treatment with an inhibitor of GSK-3β (SB216763) in combination with imatinib was found to decrease CML stem cells in vitro (as assessed by leukemic LTCIC), but this might be mediated by effects on other substrates such as p27. 74 …”