title: The histone methyltransferase DOT1L: regulatory functions and a cancer therapy target.
abstract: DOT1L is a unique histone methyltransferase that targets the histone H3 lysine 79 (H3K79) residue for mono-, di- and tri- methylation. Histone H3K79 mono- and di-methylation results in active gene transcription, while H3K79 tri-methylation is associated with gene repression. DOT1L has a critical role in regulating gene transcription, development, cell cycle progression, somatic reprogramming and DNA damage repair. DOT1L interacts with Mixed Lineage Leukemia (MLL) fusion proteins, leading to enhanced H3K79 methylation, maintenance of open chromatin, overexpression of downstream oncogenes and leukemogenesis. Importantly, small molecule DOT1L inhibitors have been recently developed, and one of the DOT1L inhibitors is already under investigation in a Phase I clinical trial in patients with MLL fusion gene-driven leukemia.
authors.affiliation: Children's Cancer Institute Australia for Medical Research Randwick NSW 2031, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wong
authors.affiliation: Department of Pathology and Inflammation and Infection Research Centre, School of Medical Sciences, UNSW Australia Kensington NSW 2052, Australia.
authors.forename: Patsie
authors.initials: P
authors.lastname: Polly
authors.affiliation: Children's Cancer Institute Australia for Medical Research Randwick NSW 2031, Australia ; School of Women's & Children's Health, University of New South Wales Randwick NSW 2031, Australia.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
keywords: DOT1L; DOT1L inhibitors; gene transcription; histone methylation; mixed lineage leukemia