DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia. Nat Med 2015 Apr;21(4):335-43
Date
03/31/2015Pubmed ID
25822366Pubmed Central ID
PMC4390532DOI
10.1038/nm.3832Scopus ID
2-s2.0-84926628784 (requires institutional sign-in at Scopus site) 175 CitationsAbstract
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.
Author List
Chen CW, Koche RP, Sinha AU, Deshpande AJ, Zhu N, Eng R, Doench JG, Xu H, Chu SH, Qi J, Wang X, Delaney C, Bernt KM, Root DE, Hahn WC, Bradner JE, Armstrong SAAuthor
Nan Zhu PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AllelesAnimals
Cell Line, Tumor
Cell Proliferation
Chromatin
Epigenesis, Genetic
Female
Gene Expression Profiling
Gene Expression Regulation, Leukemic
Gene Rearrangement
Gene Silencing
Genome
Green Fluorescent Proteins
Histone-Lysine N-Methyltransferase
Histones
Leukemia
Methyltransferases
Mice
Mice, Inbred C57BL
Myeloid-Lymphoid Leukemia Protein
Protein Binding
RNA Interference
Sirtuin 1