Abstract
Chronic myeloid leukemia (CML) is initiated and maintained by the tyrosine kinase BCR-ABL which activates a number of signal transduction pathways, including PI3K/AKT signaling and consequently inactivates FOXO transcription factors. ABL-specific tyrosine kinase inhibitors (TKIs) induce minimal apoptosis in CML progenitor cells, yet exert potent antiproliferative effects, through as yet poorly understood mechanisms. Here, we demonstrate that in CD34+ CML cells, FOXO1 and 3a are inactivated and relocalized to the cytoplasm by BCR-ABL activity. TKIs caused a decrease in phosphorylation of FOXOs, leading to their relocalization from cytoplasm (inactive) to nucleus (active), where they modulated the expression of key FOXO target genes, such as Cyclin D1, ATM, CDKN1C, and BCL6 and induced G1 arrest. Activation of FOXO1 and 3a and a decreased expression of their target gene Cyclin D1 were also observed after 6 days of in vivo treatment with dasatinib in a CML transgenic mouse model. The over-expression of FOXO3a in CML cells combined with TKIs to reduce proliferation, with similar results seen for inhibitors of PI3K/AKT/mTOR signaling. While stable expression of an active FOXO3a mutant induced a similar level of quiescence to TKIs alone, shRNA-mediated knockdown of FOXO3a drove CML cells into cell cycle and potentiated TKI-induced apoptosis. These data demonstrate that TKI-induced G1 arrest in CML cells is mediated through inhibition of the PI3K/AKT pathway and reactivation of FOXOs. This enhanced understanding of TKI activity and induced progenitor cell quiescence suggests that new therapeutic strategies for CML should focus on manipulation of this signaling network. Stem Cells 2014;32:2324–2337
Highlights
Chronic myeloid leukemia (CML) arises when the t(9;22) translocation occurs in a normal hemopoietic stem cell (HSC), generating the Philadelphia (Ph) chromosome
FOXOs are active in the nucleus, to investigate FOXO3a activity, subcellular localization was performed comparing chronic phase (CP) CML and normal progenitor cells (CD341) (Fig. 1A, left)
We have previously shown that when CML CD341 cells are exposed to tyrosine kinase inhibitors (TKIs) in vitro this leads to increased numbers of quiescent CD341 CML cells compared to untreated cells [11, 12, 34]
Summary
Chronic myeloid leukemia (CML) arises when the t(9;22) translocation occurs in a normal hemopoietic stem cell (HSC), generating the Philadelphia (Ph) chromosome. First line therapies for CML involve the protein tyrosine kinase inhibitors (TKIs) imatinib mesylate, dasatinib, and nilotinib These agents induce rapid cytogenetic responses (CyR) in the majority of CML patients in chronic phase (CP) [2], but in most cases do not eliminate BCR-ABL transcripts, suggesting persistence of residual disease. Residual disease has been definitively demonstrated in CML patients in CyR [3] and even in those rare patients who achieve and maintain a complete molecular response [4] These findings, together with the rapid kinetics of recurrence in most patients who discontinue TKIs, suggest the presence of leukemic stem/progenitor cells that are TKIinsensitive [5,6,7,8]. Assuming these effects are replicated within the bone marrow (BM) microenvironment in patients, eradication of CML may be made even more difficult as TKIs may activate cellular pathways in vivo that lead to G1 arrest and a protective state of induced quiescence
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