J Exp Clin Cancer Res (2025). https://doi.org/10.1186/ s13046-025-03588-0
题目：
A novel regulatory circuit of ATG4B and SESN3 promotes T cell leukemogenesis
作者：
Wenjuan Ma,a,*Lei Zhang,a,*Haixia Zhou,b,*Xiuyan Zhang,a,*, Xingjie Qin,aYan Wan,aRongyao Ma,a Xueyan Song,aXiaonan Zhou,aHong Liu,bBo Hu,cDepei Wu,b,cJianrong Wang,a,dXiaoyan Jiang,e Yun Zhaoa,d,f
单位：
a Cyrus Tang Medical Institute, National Clinical Research Center for Hematologic Diseases,Collaborative Innovation Center of Hematology,Soochow University,Suzhou 215123, China
b The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou 215006, China
c Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China
d Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou 215200, China
e Terry Fox Laboratory, British Columbia Cancer Research Institute and Department of Medical Genetics, University of British Columbia, Vancouver,BC, V5Z 1L3, Canada
f NHC Key Laboratory of Thrombosis and Hemostasis, MOE Engineering Center of Hematological Disease,Soochow University, Suzhou 215006, China
摘要：
Background： T cell acute lymphoblastic leukemia is a fatal hematological malignancy. Despite the treatment progress, no targeted therapy is available currently, which urges to deepen the understanding of the underlying mechanism of T-ALL cell growth/survival. Autophagy is a conserved cellular process, which plays a dual role in human cancers. Nevertheless, many aspects of the involvement of autophagy in T-ALL are not fully understood.
Methods： T-ALL patient cells and normal control cells were subjected to RT-qPCR analysis. Gene silence and overexpression was used to study the function of ATG4B and sestrin 3 (SESN3) in T-ALL cells. Atg4b deficient mice were used to study the role of Atg4b in normal hematopoietic cells and T cell development. The efficacy of S130, an ATG4B inhibitor to suppress T-ALL cell growth was evaluated in xenograft models.
Results：The results showed that the expression of several autophagy-related genes (especially ATG4B) was significantly higher in T-ALL patient cells than control cells. ATG4B ablation decreased autophagic flux and inhibited T-ALL cell growth. In contrast, Atg4b depletion had mild effects on normal hematopoiesis and T cell development. RNA-seq data and subsequent studies revealed a novel regulatory circuit of ATG4B and SESN3, and the results indicated that SESN3 hampered T-ALL cell growth via the inhibition of both mTOR/S6K/protein synthesis pathway and autophagy. Importantly, S130 exhibited anti-leukemia activity in xenograft models. A Conclusions：The present study demonstrates that a novel ATG4B-SESN3 regulatory circuit plays a crucial role in T cell leukemogenesis, which suggests that targeting ATG4B is a promising strategy for T-ALL treatment.
