Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-lineage Leukemia

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2014 Jan 7

PMID 24389101

Citations 172

Authors

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

Affiliations

Soon will be listed here.

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.

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