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Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia

Cao, F and Townsend, EC and Karatas, H and Xu, J and Li, L and Lee, S and Liu, L and Chen, Y and Ouillette, P and Zhu, J and Hess, JL and Atadja, P and Lei, M and Qin, ZS and Malek, S and Wang, S and Dou, Y (2014) Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia. MOLECULAR CELL. pp. 247-261.

Abstract

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

Item Type: Article
Additional Information: NIBR author: Atadja, P institute: NIBR contributor address: Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA ; Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA, Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA, Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA shaomeng@umich.edu; Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA ; 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 ; Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA, Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA ; Chinese Acad Sci, Interdisciplinary Res Ctr Biol & Chem, Shanghai 200032, Peoples R China ; Indiana Univ Sch Med, Indianapolis, IN 46202 USA ; Shanghai Novartis Res Inc, Novartis Inst BioMed Res, Shanghai 201203, Peoples R China ; 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, Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA ; Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA, Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA yalid@umich.edu; Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA; Wang, S M; Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22616

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