JAK2V617F+ 单链DNA调节了骨髓增殖性瘤中的外体体复杂活性和DNA感应途径
Esra Nur Demirtaş1,2, Ipek Naz Kadioglu3, Selçuk Sözer1
1Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul 34093, Turkiye.
Molecular therapy. Nucleic acids
|November 17, 2025
概括
来自费城染色体阴性髓增殖性新生瘤 (Ph-MPNs) 的单链DNA (ssDNA) 激活炎症途径,并改变健康细胞中的RNA外体复杂基因表达,提供潜在的治疗点.
科学领域:
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
- 免疫学 免疫学 免疫学
背景情况:
- 费城染色体阴性髓增殖性新生瘤 (Ph-MPNs) 涉及过度的髓细胞增殖,由像JAK2V617F.这样的突变驱动.
- 这种突变导致基因组不稳定性和单链DNA (ssDNA) 的细胞质积累.
- 通过降解受损的RNA和处理ssDNA,RNA-外基因组复合体对基因组稳定性至关重要.
研究的目的:
- 调查JAK2V617F阳性ssDNA对DNA感应通路和外体细胞复合体活性的影响.
- 为了比较健康细胞中的这些效应与来自Ph-MPN的细胞.
主要方法:
- 一个采用带血单核细胞培养的体外模型,用来自Ph-MPN细胞系的ssDNA培养.
- 对外体复杂组分表达的分析 (例如,EXOSC1) 和DNA感知通路的激活 (例如,cGAS-STING,TLR9).
主要成果:
- Ph-MPN衍生细胞释放JAK2V617F+ ssDNA,该DNA可调节外体复杂组件并激活健康细胞中的DNA感知通路,而不会引起细胞亡.
- 发现JAK2野生型ssDNA可刺激DIS3的表达,这表明它在炎症和RNA代谢中起作用.
- 来自JAK2V617F+细胞的ssDNA改变了RNA-外基因组复合体基因表达和核酸感应通路,导致MPNs的慢性炎症.
结论:
- 由JAK2V617F+细胞释放的ssDNA影响RNA-外基因组复合体基因表达和DNA感应途径.
- 这种相互作用有助于在骨髓增殖性瘤中观察到的慢性炎症.
- 该研究确定了MPNs中调节炎症和基因组不稳定的潜在治疗点.
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