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

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

Liling Wan ¹ ² ³, Hong Wen ⁴ ⁵, Yuanyuan Li ⁶ ⁷, Jie Lyu ⁸, Yuanxin Xi ⁸, Takayuki Hoshii ² ³, Julia K Joseph ¹, Xiaolu Wang ⁴, Yong-Hwee E Loh ⁹, Michael A Erb ¹⁰, Amanda L Souza ¹⁰, James E Bradner ¹⁰ ¹¹, Li Shen ⁹, Wei Li ⁸, Haitao Li ⁶ ⁷, C David Allis ¹, Scott A Armstrong ² ³, Xiaobing Shi ⁴ ⁵ ¹²

Affiliations

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.

PMID: 28241141 DOI: 10.1038/nature21687

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.

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