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Dasatinib induces endothelial-to-mesenchymal transition in human vascular-endothelial cells: counteracted by cotreatment with bosutinib

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Abstract

Adverse vascular events have become a serious clinical problem in chronic myeloid leukemia (CML) patients who receive certain BCR/ABL1 tyrosine kinase inhibitors (TKIs). Studies have shown that endothelial-to-mesenchymal transition (EndMT) can contribute to various vascular diseases. We investigated the effects of TKIs on the development of EndMT in human vascular-endothelial cells (VECs). Exposure of VECs to dasatinib, but not to other TKIs, produced a significant increase in the formation of spindle-shaped cells. This effect was accompanied by a significant increase in expression of the EndMT inducer transforming growth factor-β (TGF-β) and mesenchymal markers vimentin, smooth muscle alpha-actin, and fibronectin, as well as a significant decrease in expression of vascular-endothelial markers CD31 and VE-cadherin attributable at least in part to activation of ERK signaling. Inhibitors of TGF-β and ERK partially attenuated dasatinib-induced EndMT. Interestingly, bosutinib efficiently counteracted dasatinib-induced EndMT and attenuated dasatinib-induced phosphorylation of ERK. Taken together, these results show that dasatinib induces EndMT, which might contribute to the development of vascular toxicity, such as the pulmonary hypertension observed in CML patients receiving dasatinib. Bosutinib could play a distinct role in protecting VECs from EndMT.

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Acknowledgements

This study was supported by KAKENHI (18H02844) to Ikezoe T.

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Authors and Affiliations

  1. Department of Hematology, Fukushima Medical University, Hikariga-oka 1, Fukushima, 960-1295, Japan

    Lobna Alkebsi, Xintao Wang, Hiroshi Ohkawara, Masahiko Fukatsu, Hirotaka Mori & Takayuki Ikezoe

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  1. Lobna Alkebsi
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  2. Xintao Wang
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  3. Hiroshi Ohkawara
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  4. Masahiko Fukatsu
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  5. Hirotaka Mori
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  6. Takayuki Ikezoe
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Contributions

LA performed the experiments, statistical analysis and wrote the paper; TI managed the research (funding and data) and reviewed/edited the paper; XW, HM, MF provided advice about experimental procedures and statistics; XW, HO and TI supervised the whole research project.

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Correspondence to Lobna Alkebsi.

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Alkebsi, L., Wang, X., Ohkawara, H. et al. Dasatinib induces endothelial-to-mesenchymal transition in human vascular-endothelial cells: counteracted by cotreatment with bosutinib. Int J Hematol 113, 441–455 (2021). https://doi.org/10.1007/s12185-020-03034-1

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  • DOI: https://doi.org/10.1007/s12185-020-03034-1

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