Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia

被引：255

作者：

Cao, Fang ^{[1
]}

Townsend, Elizabeth C. ^{[1
]}

Karatas, Hacer ^{[2
,3
,4
]}

Xu, Jing ^{[1
]}

Li, Li ^{[5
]}

Lee, Shirley ^{[1
]}

Liu, Liu ^{[2
,3
,4
]}

Chen, Yong ^{[6
]}

Ouillette, Peter ^{[3
,4
]}

Zhu, Jidong ^{[7
]}

Hess, Jay L. ^{[8
]}

Atadja, Peter ^{[9
]}

Lei, Ming ^{[6
,10
]}

Qin, Zhaohui S. ^{[5
]}

Malek, Sami ^{[3
,4
]}

Wang, Shaomeng ^{[2
,3
,4
]}

Dou, Yali ^{[1
,10
]}

机构：

[1] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA

[5] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA

[6] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Natl Ctr Prot Sci Shanghai,State Key Lab Mol Biol, Shanghai 200031, Peoples R China

[7] Chinese Acad Sci, Interdisciplinary Res Ctr Biol & Chem, Shanghai 200032, Peoples R China

[8] Indiana Univ Sch Med, Indianapolis, IN 46202 USA

[9] Shanghai Novartis Res Inc, Novartis Inst BioMed Res, Shanghai 201203, Peoples R China

[10] Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA

来源：

MOLECULAR CELL | 2014年 / 53卷 / 02期

基金：

美国国家卫生研究院;

关键词：

HISTONE METHYLTRANSFERASE; METHYLATION; WDR5; INHIBITION; COMPLEX; PROTEIN; DOMAIN; HEMATOPOIESIS; ASSOCIATION; DISRUPTION;

D O I：

10.1016/j.molcel.2013.12.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

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.

引用

页码：247 / 261

页数：15

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