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细胞命运决定因素Lllgl1对于急性髓性白血病的传播是必需的

Theresa Eifert¹, Chen-Jen Hsu¹, Alicia L Becker¹

¹Innere Medizin C, Universitätsmedizin Greifswald, Greifswald, Germany.

|August 16, 2023

概括

通过促进白血病干细胞的增殖和干性,LLGL1蛋白质的失活驱动急性髓性白血病 (AML) 的发展. 恢复HoxA9表达拯救了AML表型,确定LLGL1作为AML的潜在治疗标.

科学领域:

细胞生物学细胞生物学
血液形成血液形成血液形成
癌症生物学癌症生物学

背景情况:

涂复合蛋白调节了造血干细胞 (HSC) 的功能.
斯克里布尔复合体成员在血液形成中的作用取决于背景.
LLGL1 (致命巨型幼虫综合征同类型1) 在HSC自我更新中具有已知的抑制功能.

研究的目的:

研究Scribble复合蛋白,特别是LLGL1,在急性髓性白血病 (AML) 中的作用.
确定与AML中的Scribble复合体相关的潜在治疗负债.

主要方法:

基于CRISPR/Cas9的基因查被用于识别AML中的负担.
在人类和小鼠AML模型中进行LLGL1无活化.
进行了包括HoxA基因在内的基因表达分析.
进行了白血病干细胞的表型分析.

主要成果:

在AML中,LLGL1失活被确定为负担.
无效的LLGL1促进了AML的发展和扩散能力.
在AML中LLGL1的功能是跨物种和遗传背景保存的.
LLGL1的丧失导致干性相关基因表达的减少 (例如,HoxA基因) 和白血病干细胞中的类似GMP的表型.
HoxA9的重新表达挽救了AML的表型和功能.

结论:

在AML中,LLGL1是关键的依赖和潜在的治疗点.
在AML的背景下,LLGL1表现出细胞类型特定的功能.
准LLGL1可能为AML治疗提供一种新的治疗策略.

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