HBO1 is required for the maintenance of leukaemia stem cells

被引：133

作者：

MacPherson, Laura ^{[1
,2
]}

Anokye, Juliana ^{[1
]}

Yeung, Miriam M. ^{[1
]}

Lam, Enid Y. N. ^{[1
,2
]}

Chan, Yih-Chih ^{[1
,2
]}

Weng, Chen-Fang ^{[1
]}

Yeh, Paul ^{[1
,2
]}

Knezevic, Kathy ^{[1
,2
]}

Butler, Miriam S. ^{[1
,2
]}

Hoegl, Annabelle ^{[3
]}

Chan, Kah-Lok ^{[1
,2
]}

Burr, Marian L. ^{[1
,2
]}

Gearing, Linden J. ^{[4
,5
]}

Willson, Tracy ^{[4
,5
]}

Liu, Joy ^{[4
]}

Choi, Jarny ^{[4
,5
]}

Yang, Yuqing ^{[4
,5
]}

Bilardi, Rebecca A. ^{[4
,5
]}

Falk, Hendrik ^{[4
,5
,6
]}

Nghi Nguyen ^{[7
]}

Stupple, Paul A. ^{[6
,7
]}

Peat, Thomas S. ^{[6
,8
]}

Zhang, Ming ^{[4
,5
,6
]}

de Silva, Melanie ^{[4
,5
,6
]}

Carrasco-Pozo, Catalina ^{[6
,9
]}

Avery, Vicky M. ^{[6
,9
]}

Khoo, Poh Sim ^{[6
,10
]}

Dolezal, Olan ^{[6
,8
]}

Dennis, Matthew L. ^{[6
,8
]}

Nuttall, Stewart ^{[6
,8
]}

Surjadi, Regina ^{[6
,8
]}

Newman, Janet ^{[6
,8
]}

Ren, Bin ^{[6
,8
]}

Leaver, David J. ^{[7
]}

Sun, Yuxin ^{[7
]}

Baell, Jonathan B. ^{[7
,11
]}

Dovey, Oliver ^{[12
]}

Vassiliou, George S. ^{[12
,13
]}

Grebien, Florian ^{[14
]}

Dawson, Sarah-Jane ^{[1
,2
,15
]}

Street, Ian P. ^{[4
,5
,6
]}

Monahan, Brendon J. ^{[4
,5
,6
]}

Burns, Christopher J. ^{[4
,5
]}

Choudhary, Chunaram ^{[3
]}

Blewitt, Marnie E. ^{[4
,5
]}

Voss, Anne K. ^{[4
,5
]}

Thomas, Tim ^{[4
,5
]}

Dawson, Mark A. ^{[1
,2
,15
,16
]}

机构：

[1] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[2] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia

[3] Univ Copenhagen, Fac Hlth & Med Sci, Dept Prote, Novo Nordisk Fdn Ctr Prot Res, Copenhagen, Denmark

[4] Walter & Eliza Hall Inst Med Res, Melbourne, Vic, Australia

[5] Univ Melbourne, Dept Med Biol, Melbourne, Vic, Australia

[6] Canc Therapeut CRC, Melbourne, Vic, Australia

[7] Monash Univ, Monash Inst Pharmaceut Sci, Med Chem Theme, Melbourne, Vic, Australia

[8] Commonwealth Sci & Ind Res Org CSIRO, Biomed Program, Parkville, Vic, Australia

[9] Griffith Univ, Griffith Inst Drug Discovery, Discovery Biol, Nathan, Qld, Australia

[10] Childrens Canc Inst, Kensington, NSW, Australia

[11] Nanjing Tech Univ, Sch Pharmaceut Sci, Nanjing, Peoples R China

[12] Univ Cambridge, Wellcome MRC Cambridge Stem Cell Inst, Dept Haematol, Cambridge, England

[13] Wellcome Sanger Inst, Haematol Canc Genet, Cambridge, England

[14] Univ Vet Med Vienna, Inst Med Biochem, Vienna, Austria

[15] Univ Melbourne, Ctr Canc Res, Melbourne, Vic, Australia

[16] Peter MacCallum Canc Ctr, Dept Haematol, Melbourne, Vic, Australia

来源：

NATURE | 2020年 / 577卷 / 7789期

基金：

英国医学研究理事会;

关键词：

ACUTE MYELOID-LEUKEMIA; GENE-EXPRESSION; ACETYLATION; REFINEMENT; CHROMATIN; LANDSCAPE; DISCOVERY; TARGETS; BINDING; BRD4;

D O I：

10.1038/s41586-019-1835-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：266 / +

页数：21

共 56 条

[1] Towards automated crystallographic structure refinement with phenix.refine [J].

Afonine, Pavel V. ;

Grosse-Kunstleve, Ralf W. ;

Echols, Nathaniel ;

Headd, Jeffrey J. ;

Moriarty, Nigel W. ;

Mustyakimov, Marat ;

Terwilliger, Thomas C. ;

Urzhumtsev, Alexandre ;

Zwart, Peter H. ;

Adams, Paul D. .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2012, 68 :352-367

[2] The role of HOX genes in normal hematopoiesis and acute leukemia [J].

Alharbi, R. A. ;

Pettengell, R. ;

Pandha, H. S. ;

Morgan, R. .

LEUKEMIA, 2013, 27 (05) :1000-1008

[3] Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth [J].

Baell, Jonathan B. ;

Leaver, David J. ;

Hermans, Stefan J. ;

Kelly, Gemma L. ;

Brennan, Margs S. ;

Downer, Natalie L. ;

Nguyen, Nghi ;

Wichmann, Johannes ;

Mcrae, Helen M. ;

Yang, Yuqing ;

Cleary, Ben ;

Lagiakos, H. Rachel ;

Mieruszynski, Stephen ;

Pacini, Guido ;

Vanyai, Hannah K. ;

Bergamasco, Maria I. ;

May, Rose E. ;

Davey, Bethany K. ;

Morgan, Kimberly J. ;

Sealey, Andrew J. ;

Wang, Beinan ;

Zamudio, Natasha ;

Wilcox, Stephen ;

Garnham, Alexandra L. ;

Sheikh, Bilal N. ;

Aubrey, Brandon J. ;

Doggett, Karen ;

Chung, Matthew C. ;

de Silva, Melanie ;

Bentley, John ;

Pilling, Pat ;

Hattarki, Meghan ;

Dolezal, Olan ;

Dennis, Matthew L. ;

Falk, Hendrik ;

Ren, Bin ;

Charman, Susan A. ;

White, Karen L. ;

Rautela, Jai ;

Newbold, Andrea ;

Hawkins, Edwin D. ;

Johnstone, Ricky W. ;

Huntington, Nicholas D. ;

Peat, Thomas S. ;

Heath, Joan K. ;

Strasser, Andreas ;

Parker, Michael W. ;

Smyth, Gordon K. ;

Street, Ian P. ;

Monahan, Brendon J. .

NATURE, 2018, 560 (7717) :253-+

[4] BloodSpot: a database of gene expression profiles and transcriptional programs for healthy and malignant haematopoiesis [J].

Bagger, Frederik Otzen ;

Sasivarevic, Damir ;

Sohi, Sina Hadi ;

Laursen, Linea Goricke ;

Pundhir, Sachin ;

Sonderby, Casper Kaae ;

Winther, Ole ;

Rapin, Nicolas ;

Porse, Bo T. .

NUCLEIC ACIDS RESEARCH, 2016, 44 (D1) :D917-D924

[5] Epigenetic control of gene expression in leukemogenesis: Cooperation between wild type MLL and MLL fusion proteins [J].

Ballabio, Erica ;

Milne, Thomas A. .

MOLECULAR & CELLULAR ONCOLOGY, 2014, 1 (02)

[6] CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].

BENJAMINI, Y ;

HOCHBERG, Y .

JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300

[7] HoxA9 regulated Bcl-2 expression mediates survival of myeloid progenitors and the severity of HoxA9-dependent leukemia [J].

Brumatti, Gabriela ;

Salmanidis, Marika ;

Kok, Chung H. ;

Bilardi, Rebecca A. ;

Sandow, Jarrod J. ;

Silke, Natasha ;

Mason, Kylie ;

Visser, Jolanda ;

Jabbour, Anissa M. ;

Glaser, Stefan P. ;

Okamoto, Toru ;

Bouillet, Philippe ;

D'Andrea, Richard J. ;

Ekert, Paul G. .

ONCOTARGET, 2013, 4 (11) :1933-1947

[8] Sas3 and Ada2(Gcn5)-dependent histone H3 acetylation is required for transcription elongation at the de-repressed FLO1 gene [J].

Church, Michael ;

Smith, Kim C. ;

Alhussain, Mohamed M. ;

Pennings, Sari ;

Fleming, Alastair B. .

NUCLEIC ACIDS RESEARCH, 2017, 45 (08) :4413-4430

[9] MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification [J].

Cox, Juergen ;

Mann, Matthias .

NATURE BIOTECHNOLOGY, 2008, 26 (12) :1367-1372

[10]

Dai Zhiyin, 2014, F1000Res, V3, P95, DOI 10.12688/f1000research.3928.2

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