Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia

Cao F., Townsend E. C., KARATAŞ BRISTOW H., Xu J., Li L., Lee S., ...More

Molecular Cell, vol.53, no.2, pp.247-261, 2014 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 53 Issue: 2
  • Publication Date: 2014
  • Doi Number: 10.1016/j.molcel.2013.12.001
  • Journal Name: Molecular Cell
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.247-261
  • Istanbul Medipol University Affiliated: Yes


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. © 2014 Elsevier Inc.