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

Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia.

Author information

  • 1Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 2Department 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.
  • 3Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
  • 4National 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.
  • 5Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
  • 6Interdisciplinary Research Center of Biology and Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
  • 7Indiana University School of Medicine, Indianapolis, IN 46202-3082, USA.
  • 8Novartis Institutes for BioMedical Research, Shanghai Novartis Research Inc., Shanghai 201203, China.
  • 9National 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.
  • 10Department 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.
  • 11Department 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.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24389101
[PubMed - indexed for MEDLINE]
PMCID:
PMC3965208
[Available on 2015/1/23]
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