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威尼托克拉克斯和低甲基化剂通过caspase-3/GSDME介导的高性亡作用的抗白血病作用

Fanghua Ye¹, Wen Zhang¹, Chenying Fan¹

¹Department of Pediatrics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People's Republic of China.

Journal of translational medicine

|September 7, 2023

概括

维尼托克拉克斯通过激活内在的亡路径,诱导急性髓性白血病 (AML) 中的亡,从而导致GSDME裂变. 恢复GSDME表达增强了这种抗白血病作用,提供了新的治疗策略.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
免疫学免疫学免疫学

背景情况:

抑制B细胞淋巴瘤2 (Bcl-2) 代表了急性髓性白血病 (AML) 治疗的重大进展.
热,一种编程细胞死亡形式,由于其细胞毒性和免疫原性质,为抗癌提供了一种新的治疗机制.
威尼托克拉克斯 (一种Bcl-2抑制剂) 和低甲基化剂 (HMA) 的组合改善了AML的结果,但潜在的机制需要进一步阐明.

研究的目的:

为了调查venetoclax是否会在AML细胞中诱导热.
为了识别参与venetoclax诱导的细胞死亡的热致死因子蛋白质.
探索GSDME在AML的预后意义及其在venetoclax治疗反应中的作用.

主要方法:

利用西方抹杀,免疫沉,RNA干扰,CCK8和LDH测定来研究热的机制.
通过使用公共数据库和患者样本,分析了与AML预后有关的GSDME表达.
在临床前模型和临床样本中研究了GSDME脱甲基化和venetoclax治疗的联合效应.

主要成果:

威尼托克拉克斯通过 caspase-3 依赖的 GSDME 裂变诱导热,由内在的亡途径激活.
在AML中,GSDME表达被促进物甲基化抑制,低GSDME水平与预后不佳相关.
过度表达或HMA介导的GSDME恢复在AML中增强了venetoclax诱导的烧.

结论:

通过GSDME介导的热是Bcl-2抑制剂 (如venetoclax) 抗白血病活性的关键机制.
这一发现将GSDME确定为AML的潜在治疗标和生物标记物.
结果提供了关于venetoclax和HMAs在AML治疗中的疗效的机制性见解.

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