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维尼托克拉克斯反应相关基因的CRISPR屏幕识别了转录因子ZNF740作为一个关键的功能调节器

Lixia Zhang^1,2,3, Xinyue Zhou^1,2, Sajesan Aryal^1,2

¹Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA.

Cell death & disease

|August 27, 2024

概括

转录因子ZNF740调节了急性髓性白血病 (AML) 的venetoclax敏感性. 丧失ZNF740会增加抵抗力,而过度表达会通过控制NOXA和MCL-1水平来提高灵敏度.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
遗传学是一个遗传学.

背景情况:

威尼托克拉克斯是一种有前途的BCL-2抑制剂,用于急性髓性白血病 (AML) 和其他癌症.
对venetoclax的耐药性是一个重大的临床挑战,需要对反应机制有更深入的了解.
以前的研究发现了与venetoclax敏感性相关的基因,但它们的直接因果作用在很大程度上仍未被阐明.

研究的目的:

系统地识别使用CRISPR淘汰屏幕在AML中直接调节venetoclax反应的基因.
阐明分子机制,通过确定调节剂影响venetoclax灵敏度.
确定ZNF740作为克服venetoclax耐药性的新疗法标.

主要方法:

进行了大规模的CRISPR淘汰屏幕,针对venetoclax敏感的AML样本中约有1400个高调的基因.
综合转录和基因组分析以确定直接的基因标和调控途径.
进行了体内研究,以评估ZNF740缺乏AML模型中的双重向策略的有效性.

主要成果:

鉴定了ZNF740转录因子作为venetoclax敏感性的关键调节者,一致预测了AML亚型的响应.
证明ZNF740的枯竭赋予了venetoclax的耐药性,而它的过度表达增强了敏感性.
发现ZNF740直接向NOXA,它会负面调节MCL-1的稳定性,从而控制venetoclax的反应.

结论:

ZNF740是一种新型的转录因子,通过调节NOXA-MCL-1轴来因果调节AML中的venetoclax敏感性.
恢复NOXA表达或MCL-1和BCL-2的双重向可以使ZNF740缺乏AML对venetoclax重新敏感.
在AML患者中,ZNF740代表了改善venetoclax疗效的潜在治疗标.

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