title: DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia.
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.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Chen
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Koche
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Amit U
authors.initials: AU
authors.lastname: Sinha
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Aniruddha J
authors.initials: AJ
authors.lastname: Deshpande
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhu
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Rowena
authors.initials: R
authors.lastname: Eng
authors.affiliation: Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Doench
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Haiming
authors.initials: H
authors.lastname: Xu
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Chu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Delaney
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado, USA.
authors.forename: Kathrin M
authors.initials: KM
authors.lastname: Bernt
authors.affiliation: Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.affiliation: 1] Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA. [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.affiliation: 1] Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA. [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement; D020868:Gene Silencing; D016678:Genome; D049452:Green Fluorescent Proteins / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D011485:Protein Binding; D034622:RNA Interference; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D002843:Chromatin; D006657:Histones; D049452:Green Fluorescent Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; C481527:Dot1l protein, mouse; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
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