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增强FLI1可访问性介导STAG2-突变白血病发生

Jane J Xu, Viviana Scoca, Yi Chen

bioRxiv : the preprint server for biology

|April 16, 2025

概括

造血干细胞中STAG2的丧失增加了FLI1点的可访问性,从而导致白血病的发展. 这种改变的染色质结构选择了FLI1信号,促进了白血病发生和对MENIN抑制的敏感性.

科学领域:

血液学血液学血液学
癌症生物学癌症生物学
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.

背景情况:

转录因子 (TFs) 调节细胞命运,在癌症中可以失调.
FLI1对于造血干细胞/原生细胞 (HSPC) 功能至关重要,而STAG2控制其目标可访问性.
STAG2 枯竭会增强HSPC的自我更新,但其在白血病中的作用尚未完全理解.

研究的目的:

调查STAG2损失在维持FLI1目标可达性的作用及其对白血病转变的影响.
为了阐明改变的染色质结构如何在STAG2-突变白血病中选择瘤性TF信号.

主要方法:

使用小鼠模型 (Stag2/Npm1c/+) 来研究白血病发生.
在HSPC和白血病细胞中分析了染色质可访问性,TF结合 (FLI1,MENIN) 和基因表达.
在小鼠模型和人类白血病患者中检查了免疫类型.

主要成果:

在HSPC中,STAG2的损失维持了FLI1的目标可访问性,并在NPM1c白血病中增强了FLI1的结合.
具有增加FLI1可访问性的骨髓质偏差HSPCs作为转化储库,导致完全透性白血病.
缺少STAG2的NPM1c细胞显示染色质可访问性增加和干细胞/白血病基因循环,为患者的CD34+免疫类型进行丰富.
缺少STAG2的细胞表现出染色素结合的MENIN增加,以及对MENIN抑制的敏感性增加.

结论:

增强FLI1染色体可访问性是STAG2-突变白血病中干性和白血病转变的关键驱动因素.
改变的染色质结构可以选择瘤性TF活性 (FLI1) 来驱动白血病的发展并影响治疗反应.
通过增加FLI1的可访问性和对MENIN抑制的敏感性,STAG2的损失促进了白血病发生.

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