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

doi:10.1016/j.canlet.2018.05.034

	Piribedil disrupts the MLL1-WDR5 interaction and sensitizes MLL-rearranged acute myeloid leukemia (AML) to doxorubicin-induced apoptosis
	Zhang, Xiong 1; Zheng, Xingling2,3,4 ; Yang, Hong 2,3; Yan, Juan 2,3; Fu, Xuhong 2,3; Wei, Rongrui 2,3; Xu, Xiaowei 2,3; Zhang, Zhuqing 2,3; Yu, Aisong 2,3; Zhou, Kaixin 2,3; Ding, Jian1,2,3 ; Geng, Meiyu2,3 ; Huang, Xun 2,3
	2018
发表期刊	CANCER LETTERS (IF:9.1[JCR-2023],8.3[5-Year])
ISSN	0304-3835
卷号	431 页码:150-160
发表状态	已发表
DOI	10.1016/j.canlet.2018.05.034
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.
关键词	MLL leukemia Piribedil H3K4 methylation Cell cycle Apoptosis
收录类别	SCI ; SCIE
语种	英语
资助项目	Natural Science Foundation of China for Innovation Research Group[81321092]
WOS研究方向	Oncology
WOS类目	Oncology
WOS记录号	WOS:000438477500015
出版者	ELSEVIER IRELAND LTD
WOS关键词	MIXED-LINEAGE LEUKEMIA ; PROTEIN-PROTEIN INTERACTION ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; STRUCTURE-BASED OPTIMIZATION ; STEM-CELL TRANSPLANTATION ; MUTATIONS ; INHIBITORS ; METHYLTRANSFERASES ; DIFFERENTIATION ; COMPLEX
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/27409
专题	生命科学与技术学院生命科学与技术学院_特聘教授组_丁健组生命科学与技术学院_特聘教授组_耿美玉组生命科学与技术学院_博士生
通讯作者	Ding, Jian; Geng, Meiyu; Huang, Xun
作者单位	1.Nanjing Univ, Sch Life Sci, State Key Lab Pharmaceut Biotechnol, 163 Xianlin Ave, Nanjing 210023, Jiangsu, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, 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.