Ma Dan, Liu Ping, Hu Chujiao, Zhou Zhen, Wang Ping, Wang Yan, Zhang Yaming, Ran Yunsheng, Li Pinghao, Zhao Jiangyuan, Wang Jishi, Zhang Chengliang, Tang Lei
Department of Hematology, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China.
Oncogene. 2023 Jan;42(2):124-137. doi: 10.1038/s41388-022-02536-y. Epub 2022 Nov 17.
Drug resistance from BCR-ABL tyrosine kinase inhibitors (TKIs) and other chemotherapeutics results in treatment failure and disease progression in chronic myeloid leukemia (CML). However, the mechanism is still uncertain. In this study, we investigated the role of angiopoietin-1 (ANG-1) as a potential prognostic factor for drug resistance in CML. Both intracellular and secretory ANG-1 (iANG-1 and sANG-1) were overexpressed in multidrug-resistant CML samples. The IC value was higher in primary CD34 CD38 cells with more ANG-1. Silencing ANG-1significantly sensitized three TKI-resistant CML cell lines to imatinib (IM) while recombinant human ANG-1 failed to retain cell survival in vitro. This indicated the important role of iANG-1 as opposed to sANG-1 in CML drug resistance. Moreover, a similar effect was observed in xenograft mice models bearing ANG-1-silenced CML cells. Subsequently, pathway analysis and protein validation experiments showed activation of the JAK/STAT pathway and augmentation of STAT5a phosphorylation in ANG-1 restored CML cells. Upstream Src phosphorylation, which plays a crucial role in CML drug resistance, was also upregulated as a key event in iANG-1-related JAK/STAT pathway activation. In conclusion, our study elucidated a new BCR-ABL independent molecular mechanism induced by intracytoplasmic ANG-1 overexpression as a potential strategy for overcoming CML resistance.
BCR-ABL酪氨酸激酶抑制剂（TKIs）和其他化疗药物产生的耐药性会导致慢性髓性白血病（CML）治疗失败和疾病进展。然而，其机制仍不明确。在本研究中，我们调查了血管生成素-1（ANG-1）作为CML耐药潜在预后因素的作用。在多药耐药的CML样本中，细胞内和分泌型ANG-1（iANG-1和sANG-1）均过表达。ANG-1含量较高的原代CD34⁺CD38⁻细胞的半数抑制浓度（IC）值更高。沉默ANG-1可显著增强三种TKI耐药的CML细胞系对伊马替尼（IM）的敏感性，而重组人ANG-1在体外无法维持细胞存活。这表明在CML耐药中，iANG-1而非sANG-1发挥重要作用。此外，在携带ANG-1沉默的CML细胞的异种移植小鼠模型中也观察到了类似效果。随后，通路分析和蛋白质验证实验表明，在ANG-1恢复的CML细胞中，JAK/STAT通路激活，STAT5a磷酸化增强。在CML耐药中起关键作用的上游Src磷酸化，也作为iANG-1相关JAK/STAT通路激活的关键事件而上调。总之，我们的研究阐明了一种由细胞质内ANG-1过表达诱导的新的BCR-ABL非依赖性分子机制，作为克服CML耐药的潜在策略。
