WT1 facilitates the self-renewal of leukemia-initiating cells through the upregulation of BCL2L2: WT1-BCL2L2 axis as a new acute myeloid leukemia therapy target

doi:10.1186/s12967-020-02384-y

科研成果详情

题名	WT1 facilitates the self-renewal of leukemia-initiating cells through the upregulation of BCL2L2: WT1-BCL2L2 axis as a new acute myeloid leukemia therapy target
作者	Zhou, Bin 1; Jin, Xianghong 2; Jin, Weiwei 3; Huang, Xingzhou1; Wu, Yanfei1; Li, Haiying 1; Zhu, Weijian1; Qin, Xiaoyi 2; Ye, Haige2; Gao, Shenmeng1
发表日期	2020-06-24
发表期刊	JOURNAL OF TRANSLATIONAL MEDICINE 影响因子和分区
语种	英语
原始文献类型	Article
关键词	Leukemia-initiating cell Leukemia stem cell Deubiquitinase inhibitor Ubiquitin-proteasome signal Wilms' tumor-1 Self-renewal
其他关键词	WILMS-TUMOR GENE ; STEM-CELL ; DEUBIQUITINASE INHIBITION ; PURE CURCUMIN ; 1 PROTEIN ; EXPRESSION ; APOPTOSIS ; OVEREXPRESSION ; DEGRADATION ; SENSITIVITY
摘要	Background Overexpression of Wilms' tumor-1 (WT1) transcription factor facilitates proliferation in acute myeloid leukemia (AML). However, whetherWT1is enriched in the leukemia-initiating cells (LICs) and leukemia stem cells (LSCs) and facilitates the self-renewal of LSCs remains poorly understood. Methods MLL-AF9-induced murine leukemia model was used to evaluate the effect of knockdown ofwt1on the self-renewal ability of LSC. RNA sequencing was performed onWT1-overexpressing cells to selectWT1targets. Apoptosis and colony formation assays were used to assess the anti-leukemic potential of a deubiquitinase inhibitor WP1130. Furthermore, NOD/SCID-IL2R gamma (NSG) AML xenotransplantation and MLL-AF9-induced murine leukemia models were used to evaluate the anti-leukemogenic potential of WP1130 in vivo. Results We found thatwt1is highly expressed in LICs and LSCs and facilitates the maintenance of leukemia in a murine MLL-AF9-induced model of AML. WT1 enhanced the self-renewal of LSC by increasing the expression ofBCL2L2, a member ofB cell lymphoma 2(BCL2) family, by direct binding to its promoter region. Loss ofWT1impaired self-renewal ability in LSC and delayed the progression of leukemia. WP1130 was found to modify the WT1-BCL2L2 axis, and WP1130-induced anti-leukemic activity was mediated by ubiquitin proteasome-mediated destruction of WT1 protein. WP1130 induced apoptosis and decreased colony formation abilities of leukemia cells and prolonged the overall survival in the THP1-based xenograft NSG mouse model. WP1130 also decreased the frequency of LSC and prolonged the overall survival in MLL-AF9-induced murine leukemia model. Mechanistically, WP1130 induced the degradation of WT1 by positively affecting the ubiquitination of WT1 protein. Conclusions Our results indicate thatWT1is required for the development of AML. WP1130 exhibits anti-leukemic activity by inhibiting the WT1-BCL2L2 axis, which may represent a new acute myeloid leukemia therapy target.
资助项目	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81672087, 81971991]; Zhejiang Provincial Natural Science Foundation of ChinaNatural Science Foundation of Zhejiang Province [LY19H080001]; Wenzhou Municipal Sci-Tech Bureau's program [Y20180218]; Medical Health Science and Technology Project of Zhejiang Provincial Health Commission [2019KY452]
出版者	BMC
出版地	LONDON
ISSN	1479-5876
EISSN	1479-5876
卷号	18 期号:1 页码:254
DOI	10.1186/s12967-020-02384-y
页数	15
WOS类目	Medicine, Research & Experimental
WOS研究方向	Research & Experimental Medicine
WOS记录号	WOS:000545566500001
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	32580769
PMC记录号	PMC7313134
SCOPUSEID	2-s2.0-85087013062
通讯作者地址	[Gao, Shenmeng]Laboratory of Internal Medicine,First Affiliated Hospital of Wenzhou Medical University,1 Xuefubei Street, Ouhai District,Wenzhou, Zhejiang,325000,China ; [Ye, Haige]Department of Hematology,First Affiliated Hospital of Wenzhou Medical University,1 Xuefubei Street, Ouhai District,Wenzhou, Zhejiang,325000,China
Scopus学科分类	Biochemistry, Genetics and Molecular Biology (all)
TOP期刊	TOP期刊
引用统计	被引频次：4[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/15205
专题	附属第一医院
通讯作者	Ye, Haige; Gao, Shenmeng
作者单位	1.Laboratory of Internal Medicine,First Affiliated Hospital of Wenzhou Medical University,1 Xuefubei Street, Ouhai District,Wenzhou, Zhejiang,325000,China; 2.Department of Hematology,First Affiliated Hospital of Wenzhou Medical University,1 Xuefubei Street, Ouhai District,Wenzhou, Zhejiang,325000,China; 3.Department of Obstetrics and Gynecology,Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine,Wenzhou, Zhejiang,325000,China
第一作者单位	附属第一医院
通讯作者单位	附属第一医院
第一作者的第一单位	附属第一医院
推荐引用方式 GB/T 7714	Zhou, Bin,Jin, Xianghong,Jin, Weiwei,et al. WT1 facilitates the self-renewal of leukemia-initiating cells through the upregulation of BCL2L2: WT1-BCL2L2 axis as a new acute myeloid leukemia therapy target[J]. JOURNAL OF TRANSLATIONAL MEDICINE,2020,18(1):254.
APA	Zhou, Bin., Jin, Xianghong., Jin, Weiwei., Huang, Xingzhou., Wu, Yanfei., ... & Gao, Shenmeng. (2020). WT1 facilitates the self-renewal of leukemia-initiating cells through the upregulation of BCL2L2: WT1-BCL2L2 axis as a new acute myeloid leukemia therapy target. JOURNAL OF TRANSLATIONAL MEDICINE, 18(1), 254.
MLA	Zhou, Bin,et al."WT1 facilitates the self-renewal of leukemia-initiating cells through the upregulation of BCL2L2: WT1-BCL2L2 axis as a new acute myeloid leukemia therapy target".JOURNAL OF TRANSLATIONAL MEDICINE 18.1(2020):254.