文章：

PROTAC介导的GSPT1降解损害急性髓系白血病中融合基因的表达

PROTAC-Mediated GSPT1 Degradation Impairs the Expression of Fusion Genes in Acute Myeloid Leukemia

原文发布日期：10 January 2025

DOI: 10.3390/cancers17020211

类型: Article

开放获取: 是

英文摘要：

Background: Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that utilize the ubiquitin–proteasome system to selectively degrade target proteins. This innovative technology has shown remarkable efficacy and specificity in degrading oncogenic proteins and has progressed through various stages of preclinical and clinical development for hematologic malignancies, including adult acute myeloid leukemia (AML). However, the application of PROTACs in pediatric AML remains largely unexplored. Methods: In this study, we show the potent effect of GSPT1 degradation against AML cells induced by either a GSPT1-selective cereblon modulator CC-90009 or by an off-target effect caused by a CDK6-PROTAC named GU3341. Results: Both in vitro and ex vivo experiments revealed that GSPT1 degradation significantly inhibited tumor growth, induced cell cycle arrest, and triggered apoptosis in two pediatric AML subtypes characterized by RUNX1::RUNX1T1 and FUS::ERG fusion genes. Furthermore, the degradation of GSPT1 impaired the expression of RUNX1::RUNX1T1 and its cooperating transcription factors RUNX1 and ERG. Similarly, GSPT1 degradation also reduced FUS::ERG fusion transcript levels in AML cells harboring the translocation t(16;24)(p11:q22). Conclusions: These findings suggest a new role of GSPT1 in regulating leukemic transcriptional networks and open a new therapeutic strategy to target leukemic fusion genes in pediatric AML patients.

摘要翻译： 

背景：蛋白水解靶向嵌合体（PROTACs）是一类利用泛素-蛋白酶体系统选择性降解靶蛋白的异双功能小分子。这一创新技术在降解致癌蛋白方面展现出卓越的疗效与特异性，已在包括成人急性髓系白血病（AML）在内的血液系统恶性肿瘤临床前及临床研究中取得阶段性进展。然而，PROTACs在儿童AML领域的应用仍处于探索阶段。方法：本研究通过GSPT1选择性cereblon调节剂CC-90009及CDK6-PROTAC分子GU3341的脱靶效应，揭示了GSPT1降解对AML细胞的强效抑制作用。结果：体外及离体实验表明，在携带RUNX1::RUNX1T1与FUS::ERG融合基因的两种儿童AML亚型中，GSPT1降解能显著抑制肿瘤生长、诱导细胞周期阻滞并触发细胞凋亡。此外，GSPT1降解可抑制RUNX1::RUNX1T1及其协同转录因子RUNX1与ERG的表达。同样，在存在t(16;24)(p11:q22)易位的AML细胞中，GSPT1降解也能降低FUS::ERG融合转录本水平。结论：本研究揭示了GSPT1在白血病转录调控网络中的新功能，为靶向儿童AML白血病融合基因治疗提供了新策略。

原文链接：

PROTAC-Mediated GSPT1 Degradation Impairs the Expression of Fusion Genes in Acute Myeloid Leukemia