Intracellular angiopoietin-1 promotes TKI-resistance via activation of JAK/STAT5 pathway in chronic myeloid leukemia
Intracellular angiopoietin-1 promotes TKI-resistance via activation of JAK/STAT5 pathway in chronic myeloid leukemia
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DOI：
10.1038/s41388-022-02536-y
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发表时间：
2022-11-17
期刊：
影响因子：
8
通讯作者：
Tang, Lei
中科院分区：
文献类型：
--
作者：
Ma, Dan;Liu, Ping;Tang, Lei
BCR-ABL 酪氨酸激酶抑制剂 (TKI) 和其他化疗药物的耐药性会导致慢性粒细胞白血病 (CML) 治疗失败和疾病进展。然而，其机制仍不确定。在这项研究中，我们研究了血管生成素-1 (ANG-1) 作为 CML 耐药性潜在预后因素的作用。细胞内和分泌型 ANG-1（iANG-1 和 sANG-1）在多重耐药 CML 样本中均过表达。 ANG-1 较多的原代 CD34(+) CD38(-) 细胞的 IC50 值较高。沉默 ANG-1 使三种 TKI 耐药 CML 细胞系对伊马替尼 (IM) 显着敏感，而重组人 ANG-1 未能在体外保留细胞存活。这表明 iANG-1 相对于 sANG-1 在 CML 耐药性中发挥着重要作用。此外，在携带 ANG-1 沉默 CML 细胞的异种移植小鼠模型中观察到类似的效果。随后，通路分析和蛋白质验证实验表明，ANG-1 恢复的 CML 细胞中 JAK/STAT 通路被激活，STAT5a 磷酸化增强。上游 Src 磷酸化在 CML 耐药性中发挥着至关重要的作用，同时也是 iANG-1 相关 JAK/STAT 通路激活中的关键事件。总之，我们的研究阐明了一种由胞质内 ANG-1 过表达诱导的新的 BCR-ABL 独立分子机制，作为克服 CML 耐药性的潜在策略。
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 IC50 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.