title: ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia.
abstract: Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs. Recognition of modified histones by 'reader' proteins constitutes a key mechanism underlying these processes; therefore, targeting such pathways holds clinical promise, as exemplified by the development of bromodomain and extra-terminal (BET) inhibitors. We recently identified the YEATS domain as an acetyl-lysine-binding module, but its functional importance in human cancer remains unknown. Here we show that the YEATS domain-containing protein ENL, but not its paralogue AF9, is required for disease maintenance in acute myeloid leukaemia. CRISPR-Cas9-mediated depletion of ENL led to anti-leukaemic effects, including increased terminal myeloid differentiation and suppression of leukaemia growth in vitro and in vivo. Biochemical and crystal structural studies and chromatin-immunoprecipitation followed by sequencing analyses revealed that ENL binds to acetylated histone H3, and co-localizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukaemia. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced the recruitment of RNA polymerase II to ENL-target genes, leading to the suppression of oncogenic gene expression programs. Notably, disrupting the functionality of ENL further sensitized leukaemia cells to BET inhibitors. Together, our data identify ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in acute myeloid leukaemia, and suggest that displacement of ENL from chromatin may be a promising epigenetic therapy, alone or in combination with BET inhibitors, for aggressive leukaemia.
authors.affiliation: Laboratory of Chromatin Biology &Epigenetics, The Rockefeller University, New York, New York 10065, USA.|Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Liling
authors.initials: L
authors.lastname: Wan
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wen
authors.affiliation: Beijing Advanced Innovation Center for Structural Biology, MOE Key Laboratory of Protein Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.|Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Lyu
authors.affiliation: Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yuanxin
authors.initials: Y
authors.lastname: Xi
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hoshii
authors.affiliation: Laboratory of Chromatin Biology &Epigenetics, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Joseph
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Yong-Hwee E
authors.initials: YE
authors.lastname: Loh
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 0221, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Erb
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 0221, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Souza
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 0221, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Beijing Advanced Innovation Center for Structural Biology, MOE Key Laboratory of Protein Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.|Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.affiliation: Laboratory of Chromatin Biology &Epigenetics, The Rockefeller University, New York, New York 10065, USA.
authors.forename: C David
authors.initials: CD
authors.lastname: Allis
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Genes and Development and Epigenetics &Molecular Carcinogenesis Graduate Programs, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Shi
mesh_terms: D000107:Acetylation; D000818:Animals; D064113:CRISPR-Cas Systems; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D005260:Female; D000072669:Gene Editing; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008239:Lysine / Q000378:metabolism; D051379:Mice; D009857:Oncogenes / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D000072417:Protein Domains; D012319:RNA Polymerase II / Q000378:metabolism; D014158:Transcription, Genetic; D035602:Transcriptional Elongation Factors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C090862:ELL protein, human; D006657:Histones; D035602:Transcriptional Elongation Factors; D012319:RNA Polymerase II; D008239:Lysine