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Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia

文献类型：期刊论文

作者Hu, Cheng-Long14,15; Chen, Bing-Yi15; Li, Zijuan15; Yang, Tianbiao12,13; Xu, Chun-Hui15; Yang, Ruirui10,11,13; Yu, Peng-Cheng15; Zhao, Jingyao9; Liu, Ting8; Liu, Na15
刊名CELL RESEARCH
出版日期2022-10-27
页码19
ISSN号1001-0602
DOI10.1038/s41422-022-00735-6
通讯作者Liu, Xiaolong(liux@sibcb.ac.cn) ; Sun, Xiao-Jian(xjsun@sibs.ac.cn) ; Zheng, Mingyue(myzheng@simm.ac.cn) ; Wang, Lan(lwang@sibs.ac.cn)
英文摘要Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A-associated protein 30 (SAP30) through two critical amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Further knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, our study reveals the mechanisms for altered epigenetic programs in AML and provides a promising targeted therapeutic strategy against AML.
WOS关键词HEMI-METHYLATED DNA ; TRANSCRIPTION FACTOR ; SRA DOMAIN ; UHRF1 CONTROLS ; SELF-RENEWAL ; AML1-ETO ; BINDING ; SAP30 ; DIFFERENTIATION ; CLASSIFICATION
资助项目National Key RD Plan of China[2018YFA0107200] ; National Key RD Plan of China[2018YFA0800203] ; National Key RD Plan of China[2018YFA0107802] ; National Natural Science Foundation of China General Program[81970150] ; National Natural Science Foundation of China General Program[82170156] ; Shanghai Science and Technology Innovation Action Plan Excellent Academic/Technical Leader Program (Youth)[21XD1424500] ; Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research[2019CXJQ01] ; Samuel Waxman Cancer Research Foundation ; Shanghai Guangci Translational Medical Research Development Foundation ; Lingang Laboratory[LG202102-01]
WOS研究方向Cell Biology
语种英语
出版者SPRINGERNATURE
WOS记录号WOS:000876032400001
源URL[http://119.78.100.183/handle/2S10ELR8/303023]  
专题新药研究国家重点实验室
通讯作者Liu, Xiaolong; Sun, Xiao-Jian; Zheng, Mingyue; Wang, Lan
作者单位1.Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 10, Dept Hematol, Sch Med, Shanghai, Peoples R China
2.Fudan Univ, Hosp Obstet & Gynecol, Shanghai Med Coll, Shanghai, Peoples R China
3.Shanghai Jiao Tong Univ Affiliated Peoples Hosp 6, Dept Hematol, Shanghai, Peoples R China
4.Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, Shanghai, Peoples R China
5.Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China
6.Fudan Univ, Dept Lymphoma, Shanghai Canc Ctr, Shanghai, Peoples R China
7.Fudan Univ, Sch Pharm, Shanghai, Peoples R China
8.Shanghai Jiao Tong Univ, Key Lab Pediat Hematol & Oncol, Shanghai Childrens Med Ctr, Sch Med,Dept Hematol & Oncol,Minist Hlth China, Shanghai, Peoples R China
9.Chinese Acad Sci, Univ Chinese Acad Sci, State Key Lab Cell Biol, Ctr Excellence Mol Cell Sci,Shanghai Inst Biochem, Shanghai, Peoples R China
10.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Hu, Cheng-Long,Chen, Bing-Yi,Li, Zijuan,et al. Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia[J]. CELL RESEARCH,2022:19.
APA Hu, Cheng-Long.,Chen, Bing-Yi.,Li, Zijuan.,Yang, Tianbiao.,Xu, Chun-Hui.,...&Wang, Lan.(2022).Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia.CELL RESEARCH,19.
MLA Hu, Cheng-Long,et al."Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia".CELL RESEARCH (2022):19.

入库方式： OAI收割

来源：上海药物研究所

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