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MLL1 and MLL1 fusion proteins play distinct roles in regulating leukemic transcription program

Xu, Jing and Li, Li and Xiong, Jie and Dekker, Aaron den and Ye, Andrew and Karatas , Hacer and Liu, Liu and Wang, He and Qin, Zhaohui S. and Wang, Shaomeng and Dou, Yali (2016) MLL1 and MLL1 fusion proteins play distinct roles in regulating leukemic transcription program. Cell discovery.

Abstract

MLL1 plays a critical role in mixed lineage leukemia (MLL) and is a validated therapeutic target. However, its role in global gene regulation and its functional interaction with MLL1 fusion proteins in MLL remain unclear. Here we show that despite shared DNA binding and cofactor interacting domains at N-terminus, MLL1 and MLL-AF9 are recruited to distinct chromatin regions and have divergent functions in regulating the leukemic transcription program. We demonstrate that MLL1, probably through C-terminal interaction with WDR5, is recruited to regulatory enhancers that are enriched for binding sites of ETS family transcription factors while MLL-AF9 binds to chromatin regions that have no enrichment for H3K4me1. Transcriptome-wide changes induced by different small molecule inhibitors also highlight the distinct functions of MLL1 and MLL-AF9. Taken together, our studies provide novel insights on how MLL1 and MLL-fusion proteins contribute to leukemic gene expression, which have implications in developing effective therapies in future.

Item Type: Article
Keywords: acute myeloid leukemia; epigenetic therapeutics; menin; MLL1; MLL fusion proteins
Date Deposited: 25 May 2016 23:45
Last Modified: 25 May 2016 23:45
URI: https://oak.novartis.com/id/eprint/26237

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