[en] T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant leukemia with extremely limited treatment for relapsed patients. N6-methyladenosine (m6A) reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) participates in the initiation and growth of cancers by communicating with various targets. Here, we found IGF2BP2 was highly expressed in T-ALL. Gain and loss of IGF2BP2 demonstrated IGF2BP2 was essential for T-ALL cell proliferation in vitro and loss of IGF2BP2 prolonged animal survival in a human T-ALL xenograft model. Mechanistically, IGF2BP2 directly bound to T-ALL oncogene NOTCH1 via an m6A dependent manner. Furthermore, we identified a small-molecule IGF2BP2 inhibitor JX5 and treatment of T-ALL with JX5 showed similar functions as knockdown of IGF2BP2. These findings not only shed light on the role of IGF2BP2 in T-ALL, but also provide an alternative γ‑Secretase inhibitors (GSI) therapy to treat T-ALL.
Disciplines :
Hematology
Author, co-author :
Feng, Panpan ✱; Department of Hematology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China ; Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
Chen, Dawei ✱; Université de Liège - ULiège > GIGA ; Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
Wang, Xia; Laboratory of Translational Gastroenterology, Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
Li, Yanxia; Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
Li, Zhenyu; Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250012, China
Li, Boya; Department of Hematology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
Zhang, Yupeng; Department of molecular plant biology, Norwegian Institute of Bioeconomy Research, Oslo, 1431 Ås, Norway
Li, Wei; Department of Hematology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
Zhang, Jingru; Department of Hematology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
Ye, Jingjing; Department of Hematology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
Zhao, Baobing ; Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. baobingzh@sdu.edu.cn ; Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. baobingzh@sdu.edu.cn
Li, Jingxin ; Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. ljingxin@sdu.edu.cn
Ji, Chunyan ; Department of Hematology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China. jichunyan@sdu.edu.cn
NSCF - National Natural Science Foundation of China
Funding text :
We would like to acknowledge Prof. Yin-yuan Mo and Prof. Liu Yang for their kind donate of IGF2BP2 plasmid, Prof. Hudan Liu for her technological support and ABLife team for their helpful discussions. This work was supported by grants from the Distinguished Taishan Scholars in Climbing Plan (tspd20210321), the National Natural Science Foundation of China (31971061, 82070160, 82100176), the key Program of Natural Science Foundation of Shandong Province (ZR2020KH016), the Natural Science Foundation of Shandong Province (ZR2021LSW012), the Clinical Practical new Technology and Development Fund of Qilu Hospital, Shandong University (2019-5) and the Independently Cultivate Innovative Teams of Jinan, Shandong Province (2021GXRC050).
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