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

Nat Med
Authors
Keywords
Abstract

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.

Year of Publication
2015
Journal
Nat Med
Volume
21
Issue
4
Pages
335-43
Date Published
2015 Apr
ISSN
1546-170X
URL
DOI
10.1038/nm.3832
PubMed ID
25822366
PubMed Central ID
PMC4390532
Links
Grant list
CA66996 / CA / NCI NIH HHS / United States
CA140575 / CA / NCI NIH HHS / United States
R01 CA140575 / CA / NCI NIH HHS / United States
CA176745 / CA / NCI NIH HHS / United States
P01 CA066996 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA176745 / CA / NCI NIH HHS / United States