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一个酶独立的Bcr-Abl功能,在慢性髓性白血病中调解Hsp70-Bim蛋白-蛋白相互作用

Hong Zhang¹, Ting Song¹, Yang Song²

¹Central Hospital of Dalian University of Technology, School of Pharmacy, Faculty of Medicine, Dalian University of Technology, Dalian, Liaoning 116024, China.

International journal of biological macromolecules

|April 18, 2025

概括

一个新的Bcr-Abl与Hsp70的相互作用保护耐氨酸激酶抑制剂慢性髓性白血病 (CML) 细胞免受亡. 破坏这个复合体为CML治疗提供了一个新的治疗策略.

科学领域:

分子生物学分子生物学
在瘤学瘤学.
生物化学生物化学

背景情况:

铁氨酸激酶抑制剂 (TKIs) 改变慢性髓性白血病 (CML) 的治疗方法.
一个对TKI抗性CML细胞的子集构成了治疗挑战.
Bcr-Abl激酶活性对于所有TCI耐性CML细胞的存活并不重要.

研究的目的:

研究一种新的,基因酶独立的TKI抗性在CML中的机制.
为了阐明Bcr-Abl和Hsp70在TCI耐药CML细胞中的相互作用.
确定克服TKI耐药性的潜在治疗点.

主要方法:

在体外生物物理测试:光极化测试 (FPA),异热定位热量计 (ITC),循环二极化谱学,ATPase活性测量和罗丹酶聚合抑制.
基于细胞的共免疫沉 (Co-IP).
使用Hsp70/Bim抑制剂S1g-10和Bcr-Abl PROTAC分子进行药理抑制.

主要成果:

Bcr-Abl的DNA结合域 (DBD) 与Hsp70的核酸结合域 (NBD) 相互作用,形成一个独立于Bcr-Abl激酶功能的Bcr-Abl/Hsp70/Bim三复合体.
这种相互作用增强了Hsp70对Bim的亲和力,并增加了其ATPase活性,稳定了AKT和eIF4E等生存蛋白.
复杂的药物干扰抑制了TCI耐性CML细胞的增殖.

结论:

Bcr-Abl在通过Hsp70相互作用调解TKI耐药性方面具有新的,非正规的功能.
Bcr-Abl/Hsp70/Bim复合体稳定瘤原蛋白,保护CML细胞免受亡.
针对这个复合体是一个有前途的治疗策略,用于TCI耐药CML.

关键词:

70千达尔顿的热冲击蛋白 (Hsp70) 是一种热冲击蛋白.在Bcr-Abl中使用.这是一个DNA结合域.在Hsp70-Bim中使用.非酶功能的非酶功能蛋白质与蛋白质的相互作用耐TCI慢性骨髓性白血病的慢性骨髓性白血病.

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