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2024年10月28日,中国广东省广州市广州医科大学附属第一医院Chengwu Zeng, Yangqiu Li等老师在Molecular Cancer(IF=27.7)上,在线发表题为“Combined targeting of GPX4 and BCR-ABL tyrosine kinase selectively compromises BCR-ABL+ leukemia stem cells”的论文,此论文使用了联科生物Annexin V-APC/PI Apoptosis Kit细胞凋亡试剂盒(货号:AP107)
B:BCR-ABL+ leukemia cell lines were treated with the indicated concentrations of DSF (left panel), and the percentage of Annexin V + cells was detected by the flow cytometry (right panel).D: BM MNCs from newly diagnosed patients with CML (n = 6) or BCR-ABL+ B-ALL (n = 6) were exposed to indicated concentrations of DSF for 48 h, and the percentage of Annexin V + cells was detected by the flow cytometry.
在本研究中,作者通过进行免疫荧光、共免疫沉淀(CO-IP)、RNA测序、脂质过氧化等实验证明了二硫氯噻吨(DSF)在选择性地对BCR-ABL+细胞系产生强大细胞毒性作用,并有效抑制原代BCR-ABL+白血病细胞方面的能力。关键的是,DSF与酪氨酸激酶抑制剂(TKIs)的联合治疗能够选择性地根除TKI耐药的干细胞和耐药细胞。值得注意的是,DSF能够破坏谷胱甘肽过氧化物酶4(GPX4)的稳定性,增加可游离铁池,并加剧脂质过氧化,最终导致铁死亡。研究表明,BCR-ABL的表达引起了细胞铁代谢的变化,并增加了GPX4的表达。
此外,研究还证明了GPX4在白血病干细胞(LSC)发展以及BCR-ABL+白血病的启动/维持中的不可或缺性。机械分析进一步阐明了DSF通过减少GPX4水平、破坏其与HSPA8蛋白的结合,从而促进STUB1介导的GPX4泛素化并随后的蛋白酶体降解,克服了耐药性。此外,DSF与TKIs的联合治疗有效地靶向了BCR-ABL+爆发性细胞和药物不敏感的LSC,在小鼠模型中显著提高了生存优势。
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部分引用文献:
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参考文献:Zeng C, Nie D, Wang X, et al. Combined targeting of GPX4 and BCR-ABL tyrosine kinase selectively compromises BCR-ABL+ leukemia stem cells. Mol Cancer. 2024;23(1):240. Published 2024 Oct 28. doi:10.1186/s12943-024-02162-0
原文链接:https://link.springer.com/article/10.1186/s12943-024-02162-0