HBO1 is required for the maintenance of leukaemia stem cells

Nature. 2020 Jan;577(7789):266-270. doi: 10.1038/s41586-019-1835-6.

Laura MacPherson ¹ ², Juliana Anokye ¹, Miriam M Yeung ¹, Enid Y N Lam ¹ ², Yih-Chih Chan ¹ ², Chen-Fang Weng ¹, Paul Yeh ¹ ², Kathy Knezevic ¹ ², Miriam S Butler ¹ ², Annabelle Hoegl ³, Kah-Lok Chan ¹ ², Marian L Burr ¹ ², Linden J Gearing ⁴ ⁵, Tracy Willson ⁴ ⁵, Joy Liu ⁴, Jarny Choi ⁴ ⁵, Yuqing Yang ⁴ ⁵, Rebecca A Bilardi ⁴ ⁵, Hendrik Falk ⁴ ⁵ ⁶, Nghi Nguyen ⁷, Paul A Stupple ⁶ ⁷, Thomas S Peat ⁶ ⁸, Ming Zhang ⁴ ⁵ ⁶, Melanie de Silva ⁴ ⁵ ⁶, Catalina Carrasco-Pozo ⁶ ⁹, Vicky M Avery ⁶ ⁹, Poh Sim Khoo ⁶ ¹⁰, Olan Dolezal ⁶ ⁸, Matthew L Dennis ⁶ ⁸, Stewart Nuttall ⁶ ⁸, Regina Surjadi ⁶ ⁸, Janet Newman ⁶ ⁸, Bin Ren ⁶ ⁸, David J Leaver ⁷, Yuxin Sun ⁷, Jonathan B Baell ⁷ ¹¹, Oliver Dovey ¹², George S Vassiliou ¹² ¹³, Florian Grebien ¹⁴, Sarah-Jane Dawson ¹ ² ¹⁵, Ian P Street ⁴ ⁵ ⁶, Brendon J Monahan ⁴ ⁵ ⁶, Christopher J Burns ⁴ ⁵, Chunaram Choudhary ³, Marnie E Blewitt ⁴ ⁵, Anne K Voss ⁴ ⁵, Tim Thomas ⁴ ⁵, Mark A Dawson ¹⁶ ¹⁷ ¹⁸ ¹⁹

Affiliations

1 Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
2 Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
3 Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
4 The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
5 The Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia.
6 Cancer Therapeutics CRC, Melbourne, Victoria, Australia.
7 Medicinal Chemistry Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
8 Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program, Parkville, Victoria, Australia.
9 Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
10 Children's Cancer Institute, Kensington, New South Wales, Australia.
11 School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, China.
12 Wellcome-MRC Cambridge Stem Cell Institute, Department of Haematology, University of Cambridge, Cambridge, UK.
13 Haematological Cancer Genetics, Wellcome Sanger Institute, Cambridge, UK.
14 Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria.
15 Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia.
16 Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Mark.Dawson@petermac.org.
17 Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. Mark.Dawson@petermac.org.
18 Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia. Mark.Dawson@petermac.org.
19 Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Mark.Dawson@petermac.org.

PMID: 31827282 DOI: 10.1038/s41586-019-1835-6

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.

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