@article{29cdfd7ab9374cf5b4c39926846e0602,
title = "HBO1 is required for the maintenance of leukaemia stem cells",
abstract = "Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)1. Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings.",
author = "Laura MacPherson and Juliana Anokye and Yeung, {Miriam M.} and Lam, {Enid Y.N.} and Chan, {Yih Chih} and Weng, {Chen Fang} and Paul Yeh and Kathy Knezevic and Butler, {Miriam S.} and Annabelle Hoegl and Chan, {Kah Lok} and Burr, {Marian L.} and Gearing, {Linden J.} and Tracy Willson and Joy Liu and Jarny Choi and Yuqing Yang and Bilardi, {Rebecca A.} and Hendrik Falk and Nghi Nguyen and Stupple, {Paul A.} and Peat, {Thomas S.} and Ming Zhang and {de Silva}, Melanie and Catalina Carrasco-Pozo and Avery, {Vicky M.} and Khoo, {Poh Sim} and Olan Dolezal and Dennis, {Matthew L.} and Stewart Nuttall and Regina Surjadi and Janet Newman and Bin Ren and Leaver, {David J.} and Yuxin Sun and Baell, {Jonathan B.} and Oliver Dovey and Vassiliou, {George S.} and Florian Grebien and Dawson, {Sarah Jane} and Street, {Ian P.} and Monahan, {Brendon J.} and Burns, {Christopher J.} and Chunaram Choudhary and Blewitt, {Marnie E.} and Voss, {Anne K.} and Tim Thomas and Dawson, {Mark A.}",
note = "Funding Information: Acknowledgements We thank C. Lovitt, J. Wingerd, S. Jackson and E. Allan for their technical contributions to this project. The work in the Dawson, Blewitt and Burns laboratories was supported by the Cancer Council Victoria Venture Grant Scheme, and Dawson laboratory work was supported by project grant funding from the National Health and Medical Research Council of Australia (1085015). We thank the following funders for fellowship and grant support: Leukaemia Foundation Australia senior fellowship, Cancer Council Victoria Dunlop Fellopship and Howard Hughes Medical Institute international research scholarship (M.A.D.); Victoria Cancer Agency early-career (L.M.) and mid-career (E.Y.N.L.) fellowships; CSL Centenary fellowship (S.-J.D.), Snowdome Foundation (P.Y.), Maddie Riewoldt{\textquoteright}s Vision Foundation (Y.-C.C.), Bellberry-Viertel Senior Medical Research Fellowship (M.E.B), Novo Nordisk Foundation Hallas M{\o}ller Fellowship NNF14OC0008541 (C.C.), National Health and Medical Research Council of Australia through project grants 1081421 (J.B.B. and T.T.), 575558, 1084248 (A.K.V. and T.T.), research fellowship 1081421 (A.K.V.) and postgraduate scholarship (K.-L.C.). Salary support for M.Z., M.d.S., H.F., C.C., P.S.K., P.A.S., I.P.S. and B.J.M. was provided by the Cancer Therapeutics CRC, funded through the Australian Government{\textquoteright}s Cooperative Research Centre programme. The Novo Nordisk Foundation Center for Protein Research is supported financially by the Novo Nordisk Foundation (grant agreement NNF14CC0001). This work was made possible through the Victorian State Government Operation Infrastructure Support and Australian National Health and the Medical Research Council Research Institute Infrastructure Support Scheme. We thank the Australian Synchrotron and beamline scientists for help with data collection; this research was undertaken in part using the MX2 beamline at the Australian Synchrotron and made use of the ACRF detector. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2020",
month = jan,
day = "9",
doi = "10.1038/s41586-019-1835-6",
language = "English",
volume = "577",
pages = "266--270",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
}
