HBO1 is required for the maintenance of leukaemia stem cells

Laura MacPherson, Juliana Anokye, Miriam M. Yeung, Enid Y. N. Lam, Yih-Chih Chan, Chen-Fang Weng, Paul Yeh, Kathy Knezevic, Miriam S. Butler, Annabelle Hoegl, Kah-Lok Chan, Marian L. Burr, Linden J. Gearing, Tracy Willson, Joy Liu, Jarny Choi, Yuqing Yang, Rebecca A. Bilardi, Hendrik Falk, Nghi Nguyen, Paul A. Stupple, Thomas S. Peat, Ming Zhang, Melanie Silva, Catalina Carrasco-Pozo, Vicky M. Avery, Poh Sim Khoo, Olan Dolezal, Matthew L. Dennis, Stewart Nuttall, Regina Surjadi, Janet Newman, Bin Ren, David J. Leaver, Yuxin Sun, Jonathan B. Baell, Oliver Dovey, George S. Vassiliou, Florian Grebien, Sarah-Jane Dawson, Ian P. Street, Brendon J. Monahan, Christopher J. Burns, Chunaram Choudhary, Marnie E. Blewitt, Anne K. Voss, Tim Thomas and Mark A. Dawson ()
Additional contact information
Laura MacPherson: Peter MacCallum Cancer Centre
Juliana Anokye: Peter MacCallum Cancer Centre
Miriam M. Yeung: Peter MacCallum Cancer Centre
Enid Y. N. Lam: Peter MacCallum Cancer Centre
Yih-Chih Chan: Peter MacCallum Cancer Centre
Chen-Fang Weng: Peter MacCallum Cancer Centre
Paul Yeh: Peter MacCallum Cancer Centre
Kathy Knezevic: Peter MacCallum Cancer Centre
Miriam S. Butler: Peter MacCallum Cancer Centre
Annabelle Hoegl: University of Copenhagen
Kah-Lok Chan: Peter MacCallum Cancer Centre
Marian L. Burr: Peter MacCallum Cancer Centre
Linden J. Gearing: The Walter and Eliza Hall Institute of Medical Research
Tracy Willson: The Walter and Eliza Hall Institute of Medical Research
Joy Liu: The Walter and Eliza Hall Institute of Medical Research
Jarny Choi: The Walter and Eliza Hall Institute of Medical Research
Yuqing Yang: The Walter and Eliza Hall Institute of Medical Research
Rebecca A. Bilardi: The Walter and Eliza Hall Institute of Medical Research
Hendrik Falk: The Walter and Eliza Hall Institute of Medical Research
Nghi Nguyen: Monash University
Paul A. Stupple: Cancer Therapeutics CRC
Thomas S. Peat: Cancer Therapeutics CRC
Ming Zhang: The Walter and Eliza Hall Institute of Medical Research
Melanie Silva: The Walter and Eliza Hall Institute of Medical Research
Catalina Carrasco-Pozo: Cancer Therapeutics CRC
Vicky M. Avery: Cancer Therapeutics CRC
Poh Sim Khoo: Cancer Therapeutics CRC
Olan Dolezal: Cancer Therapeutics CRC
Matthew L. Dennis: Cancer Therapeutics CRC
Stewart Nuttall: Cancer Therapeutics CRC
Regina Surjadi: Cancer Therapeutics CRC
Janet Newman: Cancer Therapeutics CRC
Bin Ren: Cancer Therapeutics CRC
David J. Leaver: Monash University
Yuxin Sun: Monash University
Jonathan B. Baell: Monash University
Oliver Dovey: University of Cambridge
George S. Vassiliou: University of Cambridge
Florian Grebien: University of Veterinary Medicine Vienna
Sarah-Jane Dawson: Peter MacCallum Cancer Centre
Ian P. Street: The Walter and Eliza Hall Institute of Medical Research
Brendon J. Monahan: The Walter and Eliza Hall Institute of Medical Research
Christopher J. Burns: The Walter and Eliza Hall Institute of Medical Research
Chunaram Choudhary: University of Copenhagen
Marnie E. Blewitt: The Walter and Eliza Hall Institute of Medical Research
Anne K. Voss: The Walter and Eliza Hall Institute of Medical Research
Tim Thomas: The Walter and Eliza Hall Institute of Medical Research
Mark A. Dawson: Peter MacCallum Cancer Centre

Nature, 2020, vol. 577, issue 7789, 266-270

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-019-1835-6

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