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在小鼠中,Phf6截断突变通过破坏表观遗传调节驱动白血病发生

Ying Guo¹, Pinpin Sui^1,2, Hui Yang¹

¹Department of Cell Systems & Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA.

|January 26, 2026

概括

截断的PHF6蛋白在新的小鼠模型中驱动白血病发生,扩大造血干细胞并促进髓状癌症. 抑制KAT6B可以治疗这些血液性恶性瘤.

科学领域:

血液学血液学血液学
分子生物学分子生物学
癌症研究癌症研究

背景情况:

在血性恶性瘤中,PHF6的体质突变很常见.
PHF6突变,通常是移或无意义的,产生截断的蛋白质.
截断PHF6在白血病发展中的作用尚不清楚.

研究的目的:

为了研究切断PHF6在白血病发生中的功能.
开发一种小鼠模型来研究PHF6切断相关的血液恶性瘤.
为了确定这些癌症的潜在治疗点.

主要方法:

一个转基因小鼠模型 (Phf6^R274XTg) 的生成,在血液细胞中表达截断的PHF6.
血液造血干细胞/原始细胞 (HSC/HPC) 池扩张和分化分析.
在HSC/HPC的转录造型和单细胞RNA-seq.
评估H3K27ac占用率和KAT6B活动.
使用KAT6A/KAT6B抑制剂 (CTx-648) 的治疗.

主要成果:

Phf6^R274XTg小鼠发生了与人类PHF6突变白血病类似的自发性血液性恶性瘤.
截断的PHF6 (PHF6^aa1-273) 导致HSC/HPC池扩张和骨髓偏差差分化.
截断PHF6导致转录失调,并通过KAT6B改变了H3K27ac模式.
在白血病小鼠中,KAT6B抑制恢复了HSC功能并改善了生存率.

结论:

截断的PHF6在驱动白血病发生方面表现出功能增强效应.
PHF6的切断会改变HSC的功能和转录程序.
KAT6B是PHF6切断相关的血液恶性瘤的潜在治疗标.

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