title: MLL1 and MLL1 fusion proteins have distinct functions in regulating leukemic transcription program.
abstract: Mixed lineage leukemia protein-1 (MLL1) has a critical role in human MLL1 rearranged leukemia (MLLr) and is a validated therapeutic target. However, its role in regulating global gene expression in MLLr cells, as well as its interplay with MLL1 fusion proteins remains unclear. Here we show that despite shared DNA-binding and cofactor interacting domains at the 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 E-twenty-six (ETS) family transcription factors, whereas MLL-AF9 binds to chromatin regions that have no H3K4me1 enrichment. 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 for developing effective therapies in the future.
authors.affiliation: Department of Pathology, University of Michigan , Ann Arbor, MI, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University , Atlanta, GA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Michigan , Ann Arbor, MI, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Department of Pathology, University of Michigan , Ann Arbor, MI, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: denDekker
authors.affiliation: Department of Pathology, University of Michigan , Ann Arbor, MI, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ye
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Hacer
authors.initials: H
authors.lastname: Karatas
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.affiliation: China Novartis Institutes for BioMedical Research , Shanghai, China.
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University , Atlanta, GA, USA.
authors.forename: Zhaohui S
authors.initials: ZS
authors.lastname: Qin
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Yali
authors.initials: Y
authors.lastname: Dou
keywords: MLL fusion proteins; MLL1; acute myeloid leukemia; epigenetic therapeutics; menin