title: Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia.
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.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Cao
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Townsend
authors.affiliation: 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.
authors.forename: Hacer
authors.initials: H
authors.lastname: Karatas
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Shirley
authors.initials: S
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Ouillette
authors.affiliation: Interdisciplinary Research Center of Biology and Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
authors.forename: Jidong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Indiana University School of Medicine, Indianapolis, IN 46202-3082, USA.
authors.forename: Jay L
authors.initials: JL
authors.lastname: Hess
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai Novartis Research Inc., Shanghai 201203, China.
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.affiliation: 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.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
authors.forename: Zhaohui S
authors.initials: ZS
authors.lastname: Qin
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Sami
authors.initials: S
authors.lastname: Malek
authors.affiliation: 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.
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yali
authors.initials: Y
authors.lastname: Dou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015456:Leukemia, Biphenotypic, Acute / Q000201:enzymology*; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects
chemical_list: D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C587684:MM-401; D009842:Oligopeptides; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C443118:Wdr5 protein, mouse; D051788:Myeloid-Lymphoid Leukemia Protein; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse