Author
Listed:
- Laura MacPherson
(Peter MacCallum Cancer Centre
University of Melbourne)
- Juliana Anokye
(Peter MacCallum Cancer Centre)
- Miriam M. Yeung
(Peter MacCallum Cancer Centre)
- Enid Y. N. Lam
(Peter MacCallum Cancer Centre
University of Melbourne)
- Yih-Chih Chan
(Peter MacCallum Cancer Centre
University of Melbourne)
- Chen-Fang Weng
(Peter MacCallum Cancer Centre)
- Paul Yeh
(Peter MacCallum Cancer Centre
University of Melbourne)
- Kathy Knezevic
(Peter MacCallum Cancer Centre
University of Melbourne)
- Miriam S. Butler
(Peter MacCallum Cancer Centre
University of Melbourne)
- Annabelle Hoegl
(University of Copenhagen)
- Kah-Lok Chan
(Peter MacCallum Cancer Centre
University of Melbourne)
- Marian L. Burr
(Peter MacCallum Cancer Centre
University of Melbourne)
- Linden J. Gearing
(The Walter and Eliza Hall Institute of Medical Research
The University of Melbourne)
- Tracy Willson
(The Walter and Eliza Hall Institute of Medical Research
The University of Melbourne)
- Joy Liu
(The Walter and Eliza Hall Institute of Medical Research)
- Jarny Choi
(The Walter and Eliza Hall Institute of Medical Research
The University of Melbourne)
- Yuqing Yang
(The Walter and Eliza Hall Institute of Medical Research
The University of Melbourne)
- Rebecca A. Bilardi
(The Walter and Eliza Hall Institute of Medical Research
The University of Melbourne)
- Hendrik Falk
(The Walter and Eliza Hall Institute of Medical Research
The University of Melbourne
Cancer Therapeutics CRC)
- Nghi Nguyen
(Monash University)
- Paul A. Stupple
(Cancer Therapeutics CRC
Monash University)
- Thomas S. Peat
(Cancer Therapeutics CRC
Biomedical Program)
- Ming Zhang
(The Walter and Eliza Hall Institute of Medical Research
The University of Melbourne
Cancer Therapeutics CRC)
- Melanie Silva
(The Walter and Eliza Hall Institute of Medical Research
The University of Melbourne
Cancer Therapeutics CRC)
- Catalina Carrasco-Pozo
(Cancer Therapeutics CRC
Griffith University)
- Vicky M. Avery
(Cancer Therapeutics CRC
Griffith University)
- Poh Sim Khoo
(Cancer Therapeutics CRC
Children’s Cancer Institute)
- Olan Dolezal
(Cancer Therapeutics CRC
Biomedical Program)
- Matthew L. Dennis
(Cancer Therapeutics CRC
Biomedical Program)
- Stewart Nuttall
(Cancer Therapeutics CRC
Biomedical Program)
- Regina Surjadi
(Cancer Therapeutics CRC
Biomedical Program)
- Janet Newman
(Cancer Therapeutics CRC
Biomedical Program)
- Bin Ren
(Cancer Therapeutics CRC
Biomedical Program)
- David J. Leaver
(Monash University)
- Yuxin Sun
(Monash University)
- Jonathan B. Baell
(Monash University
Nanjing Tech University)
- Oliver Dovey
(University of Cambridge)
- George S. Vassiliou
(University of Cambridge
Wellcome Sanger Institute)
- Florian Grebien
(University of Veterinary Medicine Vienna)
- Sarah-Jane Dawson
(Peter MacCallum Cancer Centre
University of Melbourne
University of Melbourne)
- Ian P. Street
(The Walter and Eliza Hall Institute of Medical Research
The University of Melbourne
Cancer Therapeutics CRC)
- Brendon J. Monahan
(The Walter and Eliza Hall Institute of Medical Research
The University of Melbourne
Cancer Therapeutics CRC)
- Christopher J. Burns
(The Walter and Eliza Hall Institute of Medical Research
The University of Melbourne)
- Chunaram Choudhary
(University of Copenhagen)
- Marnie E. Blewitt
(The Walter and Eliza Hall Institute of Medical Research
The University of Melbourne)
- Anne K. Voss
(The Walter and Eliza Hall Institute of Medical Research
The University of Melbourne)
- Tim Thomas
(The Walter and Eliza Hall Institute of Medical Research
The University of Melbourne)
- Mark A. Dawson
(Peter MacCallum Cancer Centre
University of Melbourne
University of Melbourne
Peter MacCallum Cancer Centre)
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.
Suggested Citation
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 &, 2020.
"HBO1 is required for the maintenance of leukaemia stem cells,"
Nature, Nature, vol. 577(7789), pages 266-270, January.
Handle:
RePEc:nat:nature:v:577:y:2020:i:7789:d:10.1038_s41586-019-1835-6
DOI: 10.1038/s41586-019-1835-6
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Citations
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Cited by:
- Fadi J. Najm & Peter DeWeirdt & Molly M. Moore & Samantha M. Bevill & Chadi A. El Farran & Kevin A. Macias & Mudra Hegde & Amanda L. Waterbury & Brian B. Liau & Peter Galen & John G. Doench & Bradley , 2023.
"Chromatin complex dependencies reveal targeting opportunities in leukemia,"
Nature Communications, Nature, vol. 14(1), pages 1-10, December.
- Yosuke Komata & Akinori Kanai & Takahiro Maeda & Toshiya Inaba & Akihiko Yokoyama, 2023.
"MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins,"
Nature Communications, Nature, vol. 14(1), pages 1-17, December.
- Ziping Niu & Chen Chen & Siyu Wang & Congcong Lu & Zhiyue Wu & Aiyuan Wang & Jing Mo & Jianji Zhang & Yanpu Han & Ye Yuan & Yingao Zhang & Yong Zang & Chaoran He & Xue Bai & Shanshan Tian & Guijin Zha, 2024.
"HBO1 catalyzes lysine lactylation and mediates histone H3K9la to regulate gene transcription,"
Nature Communications, Nature, vol. 15(1), pages 1-15, December.
- Jayme L. Dahlin & Bruce K. Hua & Beth E. Zucconi & Shawn D. Nelson & Shantanu Singh & Anne E. Carpenter & Jonathan H. Shrimp & Evelyne Lima-Fernandes & Mathias J. Wawer & Lawrence P. W. Chung & Ayushi, 2023.
"Reference compounds for characterizing cellular injury in high-content cellular morphology assays,"
Nature Communications, Nature, vol. 14(1), pages 1-16, December.
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