Department of Hematology, Fukushima Medical University, Hikariga-oka 1, Fukushima, 960-1295, Japan.
Int J Hematol. 2021 Mar;113(3):441-455. doi: 10.1007/s12185-020-03034-1. Epub 2021 Jan 3.
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.
血管不良事件已成为接受某些 BCR/ABL1 酪氨酸激酶抑制剂 (TKI) 的慢性髓性白血病 (CML) 患者的严重临床问题。研究表明，内皮-间质转化 (EndMT) 可导致多种血管疾病。我们研究了 TKI 对人血管内皮细胞 (VEC) 中 EndMT 发展的影响。达沙替尼而非其他 TKI 暴露于 VEC 可显著增加纺锤形细胞的形成。这种作用伴随着 EndMT 诱导因子转化生长因子-β (TGF-β) 和间充质标志物波形蛋白、平滑肌α-肌动蛋白和纤维连接蛋白的表达显著增加，以及血管内皮标志物 CD31 和 VE-钙粘蛋白的表达显著降低，这归因于至少部分 ERK 信号的激活。TGF-β 和 ERK 的抑制剂部分减弱了达沙替尼诱导的 EndMT。有趣的是，博舒替尼有效地拮抗了达沙替尼诱导的 EndMT，并减弱了达沙替尼诱导的 ERK 磷酸化。总之，这些结果表明达沙替尼诱导 EndMT，这可能导致血管毒性的发展，如接受达沙替尼治疗的 CML 患者中观察到的肺动脉高压。博舒替尼可能在保护 VEC 免受 EndMT 方面发挥独特作用。
