Journal
MOLECULAR CELL
Volume 53, Issue 2, Pages 247-261Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2013.12.001
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Funding
- Stand Up to Cancer (SU2C)
- Leukemia and Lymphoma Society (LLS)
- Novartis Research Institute
- National Institutes of Health (NIH) [GM082856]
- LLS
- NIH [CA177307, HG005119]
- Howard Hughes Medical Institute (HHMI)
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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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