2. Academic Validation
  3. Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia

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.
Fang Cao 1,  Elizabeth C Townsend 1,  Hacer Karatas 2,  Jing Xu 1,  Li Li 3,  Shirley Lee 1,  Liu Liu 2,  Yong Chen 4,  Peter Ouillette 5,  Jidong Zhu 6,  Jay L Hess 7,  Peter Atadja 8,  Ming Lei 9,  Zhaohui S Qin 3,  Sami Malek 5,  Shaomeng Wang 10,  Yali Dou 11
Affiliations

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: [email protected].
  • 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: [email protected].
PMID: 24389101 DOI: 10.1016/j.molcel.2013.12.001
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.

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