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

Research output: Contribution to journalArticlepeer-review

169 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)247-261
Number of pages15
JournalMolecular Cell
Issue number2
StatePublished - Jan 23 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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