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Piribedil disrupts the MLL1-WDR5 interaction and sensitizes MLL-rearranged acute myeloid leukemia (AML) to doxorubicin-induced apoptosis

文献类型：期刊论文

作者Zhang, Xiong2; Zheng, Xingling1,3,4; Yang, Hong1,3; Yan, Juan1,3; Fu, Xuhong1,3; Wei, Rongrui1,3; Xu, Xiaowei1,3; Zhang, Zhuqing1,3; Yu, Aisong1,3; Zhou, Kaixin1,3
刊名CANCER LETTERS
出版日期2018
卷号431页码:150-160
关键词MLL leukemia Piribedil H3K4 methylation Cell cycle Apoptosis
ISSN号0304-3835
DOI10.1016/j.canlet.2018.05.034
文献子类Article
英文摘要Targeting WT MLL for the treatment of MLL-r leukemia, which is highly aggressive and resistant to chemotherapy, has been shown to be a promising strategy. However, drug treatments targeting WT MLL are lacking. We used an in vitro histone methyltransferase assay to screen a library consists of 592 FDA-approved drugs for MLL1 inhibitors by measuring alterations in HTRF signal and found that Piribedil represented a potent activity. Piribedil specifically inhibited the proliferation of MLL-r cells by inducing cell-cycle arrest, apoptosis and myeloid differentiation with little toxicity to the non-MLL cells. Mechanism study showed Piribedil blocked the MLL1-WDR5 interaction and thus selectively reduced MLL1-dependent H3K4 methylation. Importantly, MLL1 depletion induced gene expression that was similar to that induced by Piribedil and rendered the MLL-r cells resistant to Piribedil-induced toxicity, revealing Piribedil exerted anti-leukemia effects by targeting MLL1. Furthermore, both the Piribedil treatment and MLL1 depletion sensitized the MLL-r cells to doxorubicin-induced apoptosis. Our study support the hypothesis that Piribedil could serve as a new drug for the treatment of MLL-r AML and provide new insight for further optimization of targeting MLL1 HMT activity.
WOS关键词MIXED-LINEAGE LEUKEMIA ; PROTEIN-PROTEIN INTERACTION ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; STRUCTURE-BASED OPTIMIZATION ; STEM-CELL TRANSPLANTATION ; MUTATIONS ; INHIBITORS ; METHYLTRANSFERASES ; DIFFERENTIATION ; COMPLEX
资助项目Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12000000] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020326] ; Natural Science Foundation of China for Innovation Research Group[81321092]
WOS研究方向Oncology
语种英语
WOS记录号WOS:000438477500015
出版者ELSEVIER IRELAND LTD
源URL[http://119.78.100.183/handle/2S10ELR8/272307]  
专题药理学第一研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
通讯作者Ding, Jian; Geng, Meiyu; Huang, Xun
作者单位1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China;
2.Nanjing Univ, Sch Life Sci, State Key Lab Pharmaceut Biotechnol, 163 Xianlin Ave, Nanjing 210023, Jiangsu, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China;
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Xiong,Zheng, Xingling,Yang, Hong,et al. Piribedil disrupts the MLL1-WDR5 interaction and sensitizes MLL-rearranged acute myeloid leukemia (AML) to doxorubicin-induced apoptosis[J]. CANCER LETTERS,2018,431:150-160.
APA Zhang, Xiong.,Zheng, Xingling.,Yang, Hong.,Yan, Juan.,Fu, Xuhong.,...&Huang, Xun.(2018).Piribedil disrupts the MLL1-WDR5 interaction and sensitizes MLL-rearranged acute myeloid leukemia (AML) to doxorubicin-induced apoptosis.CANCER LETTERS,431,150-160.
MLA Zhang, Xiong,et al."Piribedil disrupts the MLL1-WDR5 interaction and sensitizes MLL-rearranged acute myeloid leukemia (AML) to doxorubicin-induced apoptosis".CANCER LETTERS 431(2018):150-160.

入库方式： OAI收割

来源：上海药物研究所

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