Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia PMID: 24389101

ADC Targets in Oncology

2026-04-10

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

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].

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.