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针对USP14/UCHL5:克服抗治疗FLT3-ITD阳性AML的突破性方法

Ayako Nogami^1,2, Hideki Jose Amemiya², Hiroki Fujiwara²

¹Department of Laboratory Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyoku, Tokyo 113-8510, Japan.

International journal of molecular sciences

|October 16, 2024

概括

用b-AP15或奥拉诺芬抑制USP14/UCHL5,可诱导急性髓性白血病 (AML) 细胞的亡. 这些发现为治疗耐药FLT3-ITD阳性AML提供了一个有希望的新策略.

科学领域:

血液学血液学血液学
分子生物学分子生物学
在瘤学瘤学.

背景情况:

类似FMS的氨酸激酶3 (FLT3) 内重复 (ITD) 突变与急性髓性白血病 (AML) 的不良预后和耐药性有关.
针对duebiquitinating酶为难以治疗的白血病提供了潜在的治疗途径.

研究的目的:

为了研究在FLT3-ITD阳性AML中使用b-AP15或奥拉诺芬 (AUR) 抑制泛特异性酶14 (USP14) 和泛特异性C终端酶L5 (UCHL5) 的疗效.
阐明USP14/UCHL5抑制的抗白血病作用背后的分子机制.

主要方法:

用b-AP15或AUR.治疗MV4-11细胞系和患者衍生的初级AML细胞.
评估亡诱导,FLT3通路信号发送,双化和翻译启动.
分析下游目标,包括4EBP1,MAP激酶通路,NF-E2相关因子2,BCL-XL和MCL-1.

主要成果:

无论是b-AP15还是AUR,都在FLT3-ITD阳性AML细胞中诱导了亡,这种效果由USP14敲击增强.
通过4EBP1.1.治疗可以抑制FLT3的二氧化和破坏通过4EBP1.1.的翻译启动.
观察到FLT3的下调,与压力相关的MAP激酶通路的激活,以及与NF-E2相关的2因子的增加.
过度表达的BCL-XL和MCL-1赋予了对b-AP15和AUR诱导的细胞死亡的抵抗力.

结论:

用b-AP15或AUR抑制USP14/UCHL5代表了FLT3-ITD阳性AML的一种有前途的治疗策略.
观察到的效应涉及复杂的调节机制,包括调节FLT3脱化和翻译启动.

关键词:

在FLT3-ITD阳性的AML中.在UCHL5中,UCHL5是UCHL5.美国 14 美元必须进行脱离分离.治疗抵抗性的治疗.

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