转录读取之前的替代拼接程序由imatinib在CML细胞中触发的imatinib
Paulina Podszywałow-Bartnicka1, Morgan Shine1, Jing Lin1
1Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA.
bioRxiv : the preprint server for biology
|November 24, 2025
概括
细胞应激会导致转录读透,这种现象在慢性髓性白血病 (CML) 中因伊马替尼治疗而放大. 早期的读透变化先于后期的基因表达转变,可能导致治疗抵抗.
科学领域:
- 分子生物学分子生物学
- 基因组学就是基因组学.
- 癌症研究 癌症研究
背景情况:
- 细胞应力可以诱导转录阅读,其中RNA聚合酶II扩展到基因聚氨基化位点之外.
- 这种读透现象已在各种癌症类型中观察到.
- 了解针对性治疗的早期分子反应对于改善治疗结果至关重要.
研究的目的:
- 在慢性髓性白血病 (CML) 细胞中量化转录读透.
- 描述早期细胞对针对性治疗药物伊马替尼的反应.
- 研究readthrough及其相关的mRNA异型在伊马替尼布反应和耐药性的作用.
主要方法:
- 利用新生的RNA的长读序列测序来测量转录读透率.
- 在imatinib治疗后,随着时间的推移,分析了阅读量,长度和基因特异性的变化.
- 研究了mRNA异形变异,包括读透仿真体,以及它们在CML和耐伊马替尼布细胞中的存在.
主要成果:
- 转录读透量,长度和基因特异性在伊马替尼暴露1小时内增加.
- 基因表达和替代拼接的变化后来出现,在最初的读取变化之后.
- 依赖伊马替尼的mRNA异型变化包括连接上游和下游基因外型的"阅读嵌合体".
- 在18小时后,在敏感和耐性CML细胞以及患者样本中检测到修改的mRNA异型和奇梅拉水平.
结论:
- 早期,转录读透率的快速增加发生在CML细胞中对伊马替尼的反应中.
- 这些早期的读透事件似乎先于基因表达和拼接的后期变化.
- 观察到的mRNA异型和读透嵌合体的变化表明一连串影响转录和拼接保真性.
- 这些分子变化可能会导致长期的基因表达调整和CML中伊马替尼布耐药性的发展.
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