朱恩通过稳定T细胞急性淋巴细胞白血病中的HIF1a来调解葡萄糖皮质激素耐药性
Zhijie Zhang1, Jiangzhou Shi1, Qifang Wu1
1Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan 430081, China.
iScience
|November 29, 2023
概括
在T细胞急性淋巴细胞白血病 (T-ALL) 中,JUN蛋白促进对德克萨米他的抗性. 针对JNK-JUN-HIF1α通路可能会改善T-ALL治疗结果.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 免疫学 免疫学 免疫学
背景情况:
- 德克萨米他 (Dex) 对于治疗T细胞急性淋巴细胞白血病 (T-ALL) 是至关重要的.
- 在T-ALL中Dex耐药性背后的机制在很大程度上是未知的.
- 了解耐药性途径对于改善患者预后至关重要.
研究的目的:
- 调查JUN在T-ALL中Dex抗性的作用.
- 阐明Dex抗性T-ALL中连接JUN,JNK和HIF1α的分子机制.
- 确定针对JNK-JUN-HIF1α轴的潜在治疗策略.
主要方法:
- 在Dex抗性T-ALL细胞系和患者样本中分析JUN表达.
- 为了评估Dex的敏感性,JUN进行了敲击实验.
- 在耐德克斯克隆上进行RNA测序 (RNA-seq) 和ATAC测序 (ATAC-seq).
- 对协同药物组合进行高通量选.
- 治疗点的体外和体内验证.
主要成果:
- 在抗德克斯的T-ALL中,JUN的表达上调,并与预后不佳有关.
- 在JUN knockdown中,T-ALL细胞对Dex重新敏感.
- 该JNK通路显著调节了Dex抗性细胞中的JUN上调.
- JUN与低氧诱导因子1-alpha (HIF1α) 进行了物理相互作用并稳定了它.
- 与Dex协同作用的HIF1α抑制剂在体外和体内诱导细胞死亡.
结论:
- 确定了一种涉及JNK-JUN-HIF1α轴的T-ALL中Dex耐药性的新机制.
- 通过稳定HIF1α.JUN,JUN作为Dex耐药性的关键调解者.
- 准JNK-JUN-HIF1α通路是一个有前途的治疗策略,用于克服T-ALL.中的Dex耐药性.
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