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Nature. 2017 Mar 9;543(7644):265-269. doi: 10.1038/nature21687. Epub 2017 Mar 1.

ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia.

Wan L1,2,3, Wen H4,5, Li Y6,7, Lyu J8, Xi Y8, Hoshii T2,3, Joseph JK1, Wang X4, Loh YE9, Erb MA10, Souza AL10, Bradner JE10,11, Shen L9, Li W8, Li H6,7, Allis CD1, Armstrong SA2,3, Shi X4,5,12.

Author information

1
Laboratory of Chromatin Biology &Epigenetics, The Rockefeller University, New York, New York 10065, USA.
2
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
3
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
4
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
5
Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
6
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.
7
Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China.
8
Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
9
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
10
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 0221, USA.
11
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
12
Genes and Development and Epigenetics &Molecular Carcinogenesis Graduate Programs, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA.

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.

PMID:
28241141
PMCID:
PMC5372383
DOI:
10.1038/nature21687
[Indexed for MEDLINE]
Free PMC Article

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