Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia

Fang Cao; Elizabeth C Townsend; Hacer Karatas; Jing Xu; Li Li; Shirley Lee; Liu Liu; Yong Chen; Peter Ouillette; Jidong Zhu; Jay L Hess; Peter Atadja; Ming Lei; Zhaohui S Qin; Sami Malek; Shaomeng Wang; Yali Dou

doi:10.1016/j.molcel.2013.12.001

Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia

Mol Cell. 2014 Jan 23;53(2):247-61. doi: 10.1016/j.molcel.2013.12.001. Epub 2014 Jan 2.

Authors

Fang Cao¹, Elizabeth C Townsend¹, Hacer Karatas², Jing Xu¹, Li Li³, Shirley Lee¹, Liu Liu², Yong Chen⁴, Peter Ouillette⁵, Jidong Zhu⁶, Jay L Hess⁷, Peter Atadja⁸, Ming Lei⁹, Zhaohui S Qin³, Sami Malek⁵, Shaomeng Wang¹⁰, Yali Dou¹¹

Affiliations

¹ Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
² Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
⁴ National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
⁵ Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ Interdisciplinary Research Center of Biology and Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
⁷ Indiana University School of Medicine, Indianapolis, IN 46202-3082, USA.
⁸ Novartis Institutes for BioMedical Research, Shanghai Novartis Research Inc., Shanghai 201203, China.
⁹ National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁰ Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: shaomeng@umich.edu.
¹¹ Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: yalid@umich.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Cell Cycle Checkpoints / drug effects
Cell Differentiation / drug effects
Cell Line, Tumor
Cell Proliferation
Histone Methyltransferases
Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
Histone-Lysine N-Methyltransferase / chemistry
Histone-Lysine N-Methyltransferase / genetics
Histone-Lysine N-Methyltransferase / metabolism*
Histones / metabolism*
Humans
Intracellular Signaling Peptides and Proteins
Leukemia, Biphenotypic, Acute / enzymology*
Mice
Myeloid-Lymphoid Leukemia Protein / chemistry
Myeloid-Lymphoid Leukemia Protein / genetics
Myeloid-Lymphoid Leukemia Protein / metabolism*
Oligopeptides / chemistry
Oligopeptides / physiology
Proteins / metabolism
Proto-Oncogene Proteins c-bcl-2 / metabolism
Transcriptome / drug effects

Substances

Histones
Intracellular Signaling Peptides and Proteins
MM-401
Oligopeptides
Proteins
Proto-Oncogene Proteins c-bcl-2
Wdr5 protein, mouse
Myeloid-Lymphoid Leukemia Protein
Histone Methyltransferases
Histone-Lysine N-Methyltransferase
Kmt2a protein, mouse

Associated data

PDB/4GM9
SRA/SRP033036

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding