WP1130 reveals USP24 as a novel target in T-cell acute lymphoblastic leukemia

Hao Luo; Bo Jing; Yu Xia; Yugen Zhang; Meng Hu; Haiyan Cai; Yin Tong; Li Zhou; Li Yang; Junmei Yang; Hu Lei; Hanzhang Xu; Chuanxu Liu; Yingli Wu

doi:10.1186/s12935-019-0773-6

WP1130 reveals USP24 as a novel target in T-cell acute lymphoblastic leukemia

Cancer Cell Int. 2019 Mar 13:19:56. doi: 10.1186/s12935-019-0773-6. eCollection 2019.

Authors

Hao Luo^#¹, Bo Jing^#¹, Yu Xia¹, Yugen Zhang¹, Meng Hu¹, Haiyan Cai¹, Yin Tong², Li Zhou³, Li Yang¹, Junmei Yang⁴, Hu Lei¹, Hanzhang Xu¹, Chuanxu Liu⁵, Yingli Wu¹

Affiliations

¹ 1Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China.
² 2Department of Hematology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China.
³ 3State Key Laboratory of Medical Genomics, Department of Hematology, Faculty of Medical Laboratory Science, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China.
⁴ 4Department of Clinical Laboratory, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018 China.
⁵ 5Department of Hematology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092 China.

^# Contributed equally.

Abstract

Background: T-cell acute lymphoblastic leukemia (T-ALL) is a lymphoid malignancy caused by the oncogenic transformation of immature T-cell progenitors with poor outcomes. WP1130 has shown potent activity against a variety of cancer but whether WP1130 has anti-T-ALL activity is not clear. USP24, one target of WP1130, is one of the largest deubiquitinases and its detailed mechanism is poorly understood. The aim of this study was to explore whether WP1130 could suppress T-ALL and the role of USP24 in T-ALL.

Methods: Molecular docking and cellular thermal shift assay were performed to determine whether and how WP1130 directly interact with USP24. Mitochondrial transmembrane potential assay was measured via Rhodamine 123 staining. USP24 was reactivated using the deactivated CRISPR-associated protein 9 (dCas9)-synergistic activation mediator (SAM) system. The in vivo results were examined by tumor xenografts in NOD-SCID mice. All statistical analyses were performed with the SPSS software package.

Results: WP1130 treatment decreased the viability and induces apoptosis of T-ALL cells both in vitro and in vivo. Furthermore, we demonstrated that knockdown of USP24 but not USP9X could significantly induce growth inhibition and apoptosis of T-ALL cells. Oncomine database showed that USP24 expression was upregulated in T-ALL samples and Kaplan-Meier results indicated that the USP24 was negatively but USP9X was positively associated with survival in T-ALL patients. Additionally, we proposed that WP1130 directly interacts with the activity site pocket of USP24 in T-ALL cells, which leads to the decrease of its substrates Mcl-1. Mechanistically, WP1130 induces apoptosis by accelerating the collapse of mitochondrial transmembrane potential via USP24-Mcl-1 axis.

Conclusions: Altogether, using WP1130 as a chemical probe, we demonstrate that USP24 but not USP9X is a novel target in T-ALL cells. Moreover, we uncovered that WP1130 induces apoptosis by accelerating the collapse of mitochondrial transmembrane potential via USP24-Mcl-1 axis. These results provide that USP24-Mcl-1 axis may represent a novel strategy in the treatment of T-ALL and WP1130 is a promising lead compound for developing anti-T-ALL drugs.

Keywords: Mcl-1; T-cell acute lymphoblastic leukemia; USP24; WP1130; dCas9-SAM.