Journal Article

DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia

Chu, Scott H, Armstrong, Scott A, Eng, Rowena, Doench, John G, Delaney, Christopher, Bernt, Kathrin M, Sinha, Amit U, Xu, Haiming, Koche, Richard P, Zhu, Nan, Root, David E, Qi, Jun, Hahn, William C, Bradner, James E, Deshpande, Aniruddha J, Chen, Chun-Wei, Wang, Xi

2015

Overview

The authors uncover the mechanism by which DOTL1 exerts its role as an epigenetic regulator required for leukemic progression by counteracting the effects of the chromatin regulators SIRT1 and SUV39H1. Rearrangements of MLL (encoding lysine-specific methyltransferase 2A and officially known as KMT2A ; herein referred to as MLL to denote the gene associated with mixed-lineage leukemia) generate MLL fusion proteins that bind DNA and drive leukemogenic gene expression. This gene expression program is dependent on the disruptor of telomeric silencing 1–like histone 3 lysine 79 (H3K79) methyltransferase DOT1L, and small-molecule DOT1L inhibitors show promise as therapeutics for these leukemias. However, the mechanisms underlying this dependency are unclear. We conducted a genome-scale RNAi screen and found that the histone deacetylase SIRT1 is required for the establishment of a heterochromatin-like state around MLL fusion target genes after DOT1L inhibition. DOT1L inhibits chromatin localization of a repressive complex composed of SIRT1 and the H3K9 methyltransferase SUV39H1, thereby maintaining an open chromatin state with elevated H3K9 acetylation and minimal H3K9 methylation at MLL fusion target genes. Furthermore, the combination of SIRT1 activators and DOT1L inhibitors shows enhanced antiproliferative activity against MLL -rearranged leukemia cells. These results indicate that the dynamic interplay between chromatin regulators controlling the activation and repression of gene expression could provide novel opportunities for combination therapy.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/100 / 13/31 / 38/47 / 631/67/1059/602 / 631/67/1990/283 / 631/67/69 / 64/60 / 96/100 / Alleles / Animals / Biomedicine / Cancer / Cancer Research / Cell Line, Tumor / Cell Proliferation / Chromatin - metabolism / Deoxyribonucleic acid / DNA / Enzymes / Epigenesis, Genetic / Epigenetic inheritance / Epigenetics / Female / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Leukemic / Gene Rearrangement / Gene Silencing / Genetic aspects / Genome / Green Fluorescent Proteins - metabolism / Histone-Lysine N-Methyltransferase - genetics / Histones - metabolism / Infectious Diseases / Inhibitors / Leukemia / Leukemia - genetics / Leukemia - metabolism / Medical research / Medicine, Experimental / Metabolic Diseases / Methylation / Methyltransferases - metabolism / Mice / Mice, Inbred C57BL / Molecular Medicine / Myeloid-Lymphoid Leukemia Protein - genetics / Neurosciences / Protein Binding / RNA Interference / Signal transduction / Sirtuin 1 - metabolism