Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia

	Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia
	Cao, F; Townsend, EC; Karatas, H; Xu, J; Li, L; Lee, S; Liu, L; Chen, Y; Ouillette, P; Zhu, JD
刊名	MOLECULAR CELL
	2014
卷号	53 期号:2 页码:247-261
通讯作者	Wang, SM (reprint author), Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA.,shaomeng@umich.edu
英文摘要	Here we report a comprehensive characterization of our recently developed inhibitor MM-401 that targets the MLL1 H3K4 methyltransferase activity. MM-401 is able to specifically inhibit MLL1 activity by blocking MLL1-WDR5 interaction and thus the complex assembly. This targeting strategy does not affect other mixed-lineage leukemia (MLL) family histone methyltransferases (HMTs), revealing a unique regulatory feature for the MLL1 complex. Using MM-401 and its enantiomer control MM-NC-401, we show that inhibiting MLL1 methyltransferase activity specifically blocks proliferation of MLL cells by inducing cell-cycle arrest, apoptosis, and myeloid differentiation without general toxicity to normal bone marrow cells or non-MLL cells. More importantly, transcriptome analyses show that MM-401 induces changes in gene expression similar to those of MLL1 deletion, supporting a predominant role of MLL1 activity in regulating MLL1-dependent leukemia transcription program. We envision broad applications for MM-401 in basic and translational research.
学科主题	Biochemistry & Molecular Biology ; Cell Biology
类目[WOS]	Biochemistry & Molecular Biology ; Cell Biology
关键词[WOS]	TRANSCRIPTIONAL REGULATION ; HISTONE METHYLTRANSFERASE ; FUSION PROTEINS ; METHYLATION ; COMPLEX ; WDR5 ; LEUKEMOGENESIS ; HEMATOPOIESIS ; MECHANISMS ; INHIBITION
收录类别	SCI
语种	英语
WOS记录号	WOS:000330496400008
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/151]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Cao, F,Townsend, EC,Karatas, H,et al. Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia[J]. MOLECULAR CELL,2014,53(2):247-261.
APA	Cao, F.,Townsend, EC.,Karatas, H.,Xu, J.,Li, L.,...&Dou, YL.(2014).Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia.MOLECULAR CELL,53(2),247-261.
MLA	Cao, F,et al."Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia".MOLECULAR CELL 53.2(2014):247-261.