ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia Journal Article
| Authors: | Wan, L.; Wen, H.; Li, Y.; Lyu, J.; Xi, Y.; Hoshii, T.; Joseph, J. K.; Wang, X.; Loh, Y. H. E.; Erb, M. A.; Souza, A. L.; Bradner, J. E.; Shen, L.; Li, W.; Li, H.; Allis, C. D.; Armstrong, S. A.; Shi, X. |
| Article 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 â € 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. © Macmillan Publishers Limited, part of Springer Nature. All rights reserved. |
| Journal Title: | Nature |
| Volume: | 543 |
| Issue: | 7644 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2017-03-09 |
| Start Page: | 265 |
| End Page: | 269 |
| Language: | English |
| DOI: | 10.1038/nature21687 |
| PROVIDER: | scopus |
| PMCID: | PMC5372383 |
| PUBMED: | 28241141 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 April 2017 -- Source: Scopus |
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