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Wu-5, a novel USP10 inhibitor, enhances crenolanib-induced FLT3-ITD-positive AML cell death via inhibiting FLT3 and AMPK pathways

Authors: Miao Yu1,2, Zhi-xiao Fang2, Wei-wei Wang2, Ying Zhang1,2, Zhi-lei Bu1,2, Meng Liu2, Xin-hua Xiao3, Zi-lu Zhang2,3, Xing-ming Zhang2,4, Yang Cao5, Ying-ying Wang2, Hu Lei2, Han-zhang Xu2, Yun-zhao Wu2, Wei Liu1, Ying-li Wu2
1 Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
2 Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic MedicineChemical 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
3 Department of Hematology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
4 Department of Transfusion Medicine, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
5 Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People’s Hospital of Changzhou, Changzhou 213003, China
Correspondence to: Wei Liu: bsjys@shsmu.edu.cn, Ying-li Wu: wuyingli@shsmu.edu.cn,
DOI: 10.1038/s41401-020-0455-x
Received: 31 December 2019
Accepted: 2 June 2020
Advance online: 21 July 2020

Abstract

The kinase FLT3 internal tandem duplication (FLT3-ITD) is related to poor clinical outcomes of acute myeloid leukemia (AML). FLT3 inhibitors have provided novel strategies for the treatment of FLT3-ITD-positive AML. But they are limited by rapid development of acquired resistance and refractory in monotherapy. Recent evidence shows that inducing the degradation of FLT3-mutated protein is an attractive strategy for the treatment of FLT3-ITD-positive AML, especially those with FLT3 inhibitor resistance. In this study we identified Wu-5 as a novel USP10 inhibitor inducing the degradation of FLT3-mutated protein. We showed that Wu-5 selectively inhibited the viability of FLT3 inhibitor-sensitive (MV4-11, Molm13) and -resistant (MV4-11R) FLT3-ITD-positive AML cells with IC50 of 3.794, 5.056, and 8.386 μM, respectively. Wu-5 (1−10 μM) dose-dependently induced apoptosis of MV4-11, Molm13, and MV4-11R cells through the proteasome-mediated degradation of FLT3-ITD. We further demonstrated that Wu-5 directly interacted with and inactivated USP10, the deubiquitinase for FLT3-ITD in vitro (IC50 value= 8.3 μM) and in FLT3-ITD-positive AML cells. Overexpression of USP10 abrogated Wu-5-induced FLT3-ITD degradation and cell death. Also, the combined treatment of Wu-5 and crenolanib produced synergistic cell death in FLT3-ITD-positive cells via the reduction of both FLT3 and AMPKα proteins. In support of this, AMPKα inhibitor compound C synergistically enhanced the anti-leukemia effect of crenolanib, while AMPKα activator metformin inhibited the anti-leukemia effect of crenolanib. In summary, we demonstrate that Wu-5, a novel USP10 inhibitor, can overcome FLT3 inhibitor resistance and synergistically enhance the anti-AML effect of crenolanib through targeting FLT3 and AMPKα pathway.
Keywords: AML; Wu-5; crenolanib; USP10; FLT3-ITD; AMPKα; Compound C; metformin

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