Cao, FangTownsend, Elizabeth C.Karatas, HacerXu, JingLi, LiLee, ShirleyLiu, LiuChen, YongOuillette, PeterZhu, JidongHess, Jay L.Atadja, PeterLei, MingQin, ZhaohuiMalek, SamiWang, ShaomengDou, Yali2016-04-112016-04-112014-01-23Cao, F., Townsend, E. C., Karatas, H., Xu, J., Li, L., Lee, S., … Dou, Y. (2014). Targeting MLL1 H3 K4 methyltransferase activity in MLL leukemia. Molecular Cell, 53(2), 247–261. http://doi.org/10.1016/j.molcel.2013.12.0011097-4164https://hdl.handle.net/1805/9243Here 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.en-USPublisher PolicyHistone-Lysine N-Methyltransferaseantagonists & inhibitorsmetabolismHistonesLeukemia, Biphenotypic, AcuteenzymologyMyeloid-Lymphoid Leukemia ProteinArticle