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- W2202625745 abstract "Bcr-Abl tyrosine kinase supports CML cell survival in part by regulating anti-apoptotic Bcl-2 proteins such as Bcl-xL and Mcl-1. Bcr-Abl tyrosine kinase inhibitors (TKIs) are effective for treating chronic myeloid leukemia (CML). However, they are ineffective in eliminating CML stem cells and blast crisis (BC) CML. We hypothesized that cooperative targeting of Bcl-2 and Bcr-Abl tyrosine kinase could overcome these limitations. We demonstrate that the Bcl-2- selective inhibitor ABT-199 significantly decreased the number of leukemic Lin-Sca1+cKit+ cells and of leukemia cells in various cell linages and prolonged survival in an inducible transgenic chronic-phase CML murine model (Scl-tTa-BCR-ABL). Effects were markedly enhanced when ABT-199 was combined with nilotinib. Importantly, the combination significantly abolished CML cell engraftment and CML stem cell frequency (P < 0.0001) in secondary transplant recipients, while nilotinib has no such effect. Furthermore, combinations of ABT-199 and TKIs effectively eradicated bulk, CD34+, and quiescent CD34+ stem/progenitor cells obtained from BC CML patients who were resistance to one or more TKIs clinically. Mechanistic studies demonstrated that nilotinib inhibited the expression of Bcl-xL and Mcl-1 mRNA and protein, even in cells from TKI-(including nilotinib) resistant patients. Individual inhibition of Bcl-xL or Mcl-1, and even more so inhibition of both, by siRNAs increased the sensitivity of cells to ABT-199, suggesting that cooperative inhibition of Bcl-2 by ABT-199 and Bcl-xL/Mcl-1 by TKIs contributes to the observed synergy. These results demonstrate Bcl-2 dependence of CML stem/progenitor cells and strongly suggest that this combination strategy has the potential to eradicate CML stem/progenitor cells and BC CML cells, neither of which are effectively targeted by TKIs alone and could significantly improve the therapy of and potentially cure patients with CML." @default.
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- W2202625745 date "2015-09-01" @default.
- W2202625745 modified "2023-10-15" @default.
- W2202625745 title "Combined Targeting of Bcl-2 and Bcr-Abl Tyrosine Kinase Eradicates Chronic Myeloid Leukemia Stem/Progenitor Cells" @default.
- W2202625745 doi "https://doi.org/10.1016/j.clml.2015.07.070" @default.
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