Perzolli Alicia, Steinebach Christian, Krönke Jan, Gütschow Michael, Zwaan C Michel, Barneh Farnaz, Heidenreich Olaf
Princess Maxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.
Department of Pediatric Oncology, Erasmus MC/Sophia Children's Hospital, 3015 GD Rotterdam, The Netherlands.
Cancers (Basel). 2025 Jan 10;17(2):211. doi: 10.3390/cancers17020211.
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.
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.
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).
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.
靶向蛋白降解嵌合体（PROTACs）是一类异双功能小分子，其利用泛素-蛋白酶体系统选择性降解靶蛋白。这项创新技术在降解致癌蛋白方面已显示出显著的疗效和特异性，并已在血液系统恶性肿瘤（包括成人急性髓系白血病（AML））的临床前和临床开发的各个阶段取得进展。然而，PROTACs在儿童AML中的应用在很大程度上仍未得到探索。
在本研究中，我们展示了由GSPT1选择性的脑啡肽酶调节剂CC-90009或名为GU3341的CDK6-PROTAC的脱靶效应诱导的GSPT1降解对AML细胞的强效作用。
体外和体内实验均显示，GSPT1降解显著抑制了以RUNX1::RUNX1T1和FUS::ERG融合基因为特征的两种儿童AML亚型的肿瘤生长，诱导细胞周期停滞，并引发细胞凋亡。此外，GSPT1的降解损害了RUNX1::RUNX1T1及其协同转录因子RUNX1和ERG的表达。同样，GSPT1降解也降低了携带易位t(16;24)(p11:q22)的AML细胞中FUS::ERG融合转录本水平。
这些发现提示了GSPT1在调节白血病转录网络中的新作用，并为靶向儿童AML患者白血病融合基因开辟了新的治疗策略。
