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COMAL:COhesin Mutations in Acute Leukemia: from modeling and mechanisms to novel therapeutics

Total Cost €


EC-Contrib. €






Project "COMAL" data sheet

The following table provides information about the project.


Organization address
postcode: CB2 1TN

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country United Kingdom [UK]
 Total cost 1˙999˙574 €
 EC max contribution 1˙999˙574 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2014-CoG
 Funding Scheme ERC-COG
 Starting year 2015
 Duration (year-month-day) from 2015-09-01   to  2020-08-31


Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 


 Project objective

Transcriptional dyregulation is a common driver in cancer and acute myeloid leukemia (AML) is an exemplar of this process. AML has a dismal survival rate of <30% with novel targeted therapies urgently required. My research focuses on improving our understanding of the biology of AML and using this knowledge to develop targeted therapies to improve outcomes. Recently loss-of-function mutations in members of the cohesin complex have been described in up to 15% of patients with AML. The cohesin complex mediates sister chromatid cohesion, an important process for DNA repair and proper chromosomal segregation. It has also recently been demonstrated to be important for transcriptional regulation, due to its coordination of communication between promoters and enhancer and insulator elements. Evidence suggests that transcriptional alterations underlie the mechanisms of transformation by cohesin mutations in AML. However, other evidence and my preliminary data also suggest cohesin mutant cells to have specific vulnerabilities related to their roles in proper chromosome segregation and DNA repair that can be specifically targeted.


1) Generation of mouse models of cohesin-mutated AML. To model AML in vivo and as a resources for Obj 2-4

2) Characterisation of transcriptional defects in cohesin-mutated AML using state-of-the-art genomic techniques (RNA-Seq, ChIP-Seq and Capture Hi-C)

3) Define mechanisms of cohesin-mediated transcriptional regulation in normal hematopoiesis and its alteration in leukaemia using SILAC based proteomics and ChIP-Seq co-binding

4) Therapeutic targeting of the cohesin complex in cohesin-mutant AML using compounds identified in a large screen and suggested by Obj 1-3 and tested in cell lines, patient samples and in vivo models.

This proposal will inform mechanisms of transcriptional regulation that occur during normal hematopoiesis and how these are altered in AML. It will also identify candidate therapies for this aggressive disease


year authors and title journal last update
List of publications.
2019 Daniel Sasca, Haiyang Yun, George Giotopoulos, Jakub Szybinski, Theo Evan, Nicola K. Wilson, Moritz Gerstung, Paolo Gallipoli, Anthony R. Green, Robert Hills, Nigel Russell, Cameron S. Osborne, Elli Papaemmanuil, Berthold Göttgens, Peter Campbell, Brian J. P. Huntly
Cohesin-dependent regulation of gene expression during differentiation is lost in cohesin-mutated myeloid malignancies
published pages: 2195-2208, ISSN: 0006-4971, DOI: 10.1182/blood.2019001553
Blood 134/24 2020-04-15
2019 Faisal Basheer, George Giotopoulos, Eshwar Meduri, Haiyang Yun, Milena Mazan, Daniel Sasca, Paolo Gallipoli, Ludovica Marando, Malgorzata Gozdecka, Ryan Asby, Olivia Sheppard, Monika Dudek, Lars Bullinger, Hartmut Döhner, Richard Dillon, Sylvie Freeman, Oliver Ottmann, Alan Burnett, Nigel Russell, Elli Papaemmanuil, Robert Hills, Peter Campbell, George S. Vassiliou, Brian J.P. Huntly
Contrasting requirements during disease evolution identify EZH2 as a therapeutic target in AML
published pages: 966-981, ISSN: 0022-1007, DOI: 10.1084/jem.20181276
Journal of Experimental Medicine 216/4 2020-04-15
2018 Malgorzata Gozdecka, Eshwar Meduri, Milena Mazan, Konstantinos Tzelepis, Monika Dudek, Andrew J. Knights, Mercedes Pardo, Lu Yu, Jyoti S. Choudhary, Emmanouil Metzakopian, Vivek Iyer, Haiyang Yun, Naomi Park, Ignacio Varela, Ruben Bautista, Grace Collord, Oliver Dovey, Dimitrios A. Garyfallos, Etienne De Braekeleer, Saki Kondo, Jonathan Cooper, Berthold Göttgens, Lars Bullinger, Paul A. Northcott
UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs
published pages: 883-894, ISSN: 1061-4036, DOI: 10.1038/s41588-018-0114-z
Nature Genetics 50/6 2020-04-15
2016 Thomas McKerrell, Thaidy Moreno, Hannes Ponstingl, Niccolo Bolli, João M. L. Dias, German Tischler, Vincenza Colonna, Bridget Manasse, Anthony Bench, David Bloxham, Bram Herman, Danielle Fletcher, Naomi Park, Michael A. Quail, Nicla Manes, Clare Hodkinson, Joanna Baxter, Jorge Sierra, Theodora Foukaneli, Alan J. Warren, Jianxiang Chi, Paul Costeas, Roland Rad, Brian Huntly, Carolyn Grove, Zemin Ning, Chris Tyler-Smith, Ignacio Varela, Mike Scott, Josep Nomdedeu, Ville Mustonen, George S. Vassiliou
Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies
published pages: e1-e9, ISSN: 0006-4971, DOI: 10.1182/blood-2015-11-683334
Blood 128/1 2020-01-17
2016 Omer Gilan, Enid Y N Lam, Isabelle Becher, Dave Lugo, Ester Cannizzaro, Gerard Joberty, Aoife Ward, Meike Wiese, Chun Yew Fong, Sarah Ftouni, Dean Tyler, Kym Stanley, Laura MacPherson, Chen-Fang Weng, Yih-Chih Chan, Margherita Ghisi, David Smil, Christopher Carpenter, Peter Brown, Neil Garton, Marnie E Blewitt, Andrew J Bannister, Tony Kouzarides, Brian J P Huntly, Ricky W Johnstone, Gerard Drewes, Sarah-Jane Dawson, Cheryl H Arrowsmith, Paola Grandi, Rab K Prinjha, Mark A Dawson
Functional interdependence of BRD4 and DOT1L in MLL leukemia
published pages: 673-681, ISSN: 1545-9993, DOI: 10.1038/nsmb.3249
Nature Structural & Molecular Biology 23/7 2020-01-17
2016 Konstantinos Tzelepis, Hiroko Koike-Yusa, Etienne De Braekeleer, Yilong Li, Emmanouil Metzakopian, Oliver M. Dovey, Annalisa Mupo, Vera Grinkevich, Meng Li, Milena Mazan, Malgorzata Gozdecka, Shuhei Ohnishi, Jonathan Cooper, Miten Patel, Thomas McKerrell, Bin Chen, Ana Filipa Domingues, Paolo Gallipoli, Sarah Teichmann, Hannes Ponstingl, Ultan McDermott, Julio Saez-Rodriguez, Brian J.P. Huntly, Francesco Iorio, Cristina Pina, George S. Vassiliou, Kosuke Yusa
A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia
published pages: 1193-1205, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2016.09.079
Cell Reports 17/4 2020-01-17
2017 Sarah J. Horton, George Giotopoulos, Haiyang Yun, Shabana Vohra, Olivia Sheppard, Rachael Bashford-Rogers, Mamunur Rashid, Alexandra Clipson, Wai-In Chan, Daniel Sasca, Loukia Yiangou, Hikari Osaki, Faisal Basheer, Paolo Gallipoli, Natalie Burrows, Ayşegül Erdem, Anastasiya Sybirna, Sarah Foerster, Wanfeng Zhao, Tonci Sustic, Anna Petrunkina Harrison, Elisa Laurenti, Jessica Okosun, Daniel Hodson, Penny Wright, Ken G. Smith, Patrick Maxwell, Jude Fitzgibbon, Ming Q. Du, David J. Adams, Brian J. P. Huntly
Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors
published pages: 1093-1104, ISSN: 1465-7392, DOI: 10.1038/ncb3597
Nature Cell Biology 19/9 2020-01-17
2015 George Giotopoulos, Louise van der Weyden, Hikari Osaki, Alistair G. Rust, Paolo Gallipoli, Eshwar Meduri, Sarah J. Horton, Wai-In Chan, Donna Foster, Rab K. Prinjha, John E. Pimanda, Daniel G. Tenen, George S. Vassiliou, Steffen Koschmieder, David J. Adams, Brian J.P. Huntly
A novel mouse model identifies cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression
published pages: 1551-1569, ISSN: 0022-1007, DOI: 10.1084/jem.20141661
The Journal of Experimental Medicine 212/10 2020-01-17
2015 Chun Yew Fong, Omer Gilan, Enid Y. N. Lam, Alan F. Rubin, Sarah Ftouni, Dean Tyler, Kym Stanley, Devbarna Sinha, Paul Yeh, Jessica Morison, George Giotopoulos, Dave Lugo, Philip Jeffrey, Stanley Chun-Wei Lee, Christopher Carpenter, Richard Gregory, Robert G. Ramsay, Steven W. Lane, Omar Abdel-Wahab, Tony Kouzarides, Ricky W. Johnstone, Sarah-Jane Dawson, Brian J. P. Huntly, Rab K. Prinjha, Anthony T. Papenfuss, Mark A. Dawson
BET inhibitor resistance emerges from leukaemia stem cells
published pages: 538-542, ISSN: 0028-0836, DOI: 10.1038/nature14888
Nature 525/7570 2020-01-17
2016 Neil A. Barrett, Camille Malouf, Chrysa Kapeni, Wendi A. Bacon, George Giotopoulos, Sten Eirik W. Jacobsen, Brian J. Huntly, Katrin Ottersbach
Mll-AF4 Confers Enhanced Self-Renewal and Lymphoid Potential during a Restricted Window in Development
published pages: 1039-1054, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2016.06.046
Cell Reports 16/4 2020-01-17
2016 K Kollmann, W Warsch, C Gonzalez-Arias, F L Nice, E Avezov, J Milburn, J Li, D Dimitropoulou, S Biddie, M Wang, E Poynton, M Colzani, M R Tijssen, S Anand, U McDermott, B Huntly, T Green
A novel signalling screen demonstrates that CALR mutations activate essential MAPK signalling and facilitate megakaryocyte differentiation
published pages: 934-944, ISSN: 0887-6924, DOI: 10.1038/leu.2016.280
Leukemia 31/4 2020-01-17
2018 Paolo Gallipoli, George Giotopoulos, Konstantinos Tzelepis, Ana S.H. Costa, Shabana Vohra, Paula Medina-Perez, Faisal Basheer, Ludovica Marando, Lorena Di Lisio, Joao M.L. Dias, Haiyang Yun, Daniel Sasca, Sarah J. Horton, George Vassiliou, Christian Frezza, Brian J.P. Huntly
Glutaminolysis is a metabolic dependency in FLT3 ITD acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition
published pages: blood-2017-12-82, ISSN: 0006-4971, DOI: 10.1182/blood-2017-12-820035
Blood 2020-01-17
2016 Marco Sciacovelli, Emanuel Gonçalves, Timothy Isaac Johnson, Vincent Roberto Zecchini, Ana Sofia Henriques da Costa, Edoardo Gaude, Alizee Vercauteren Drubbel, Sebastian Julian Theobald, Sandra Riekje Abbo, Maxine Gia Binh Tran, Vinothini Rajeeve, Simone Cardaci, Sarah Foster, Haiyang Yun, Pedro Cutillas, Anne Warren, Vincent Gnanapragasam, Eyal Gottlieb, Kristian Franze, Brian Huntly, Eamonn Richard Maher, Patrick Henry Maxwell, Julio Saez-Rodriguez, Christian Frezza
Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition
published pages: 544-547, ISSN: 0028-0836, DOI: 10.1038/nature19353
Nature 537/7621 2020-01-17
2017 D Beck, J A I Thoms, C Palu, T Herold, A Shah, J Olivier, L Boelen, Y Huang, D Chacon, A Brown, M Babic, C Hahn, M Perugini, X Zhou, B J Huntly, A Schwarzer, J-H Klusmann, W E Berdel, B Wörmann, T Büchner, W Hiddemann, S K Bohlander, L B To, H S Scott, I D Lewis, R J D\'Andrea, J W H Wong, J E Pimanda
A four-gene LincRNA expression signature predicts risk in multiple cohorts of acute myeloid leukemia patients
published pages: 263-272, ISSN: 0887-6924, DOI: 10.1038/leu.2017.210
Leukemia 32/2 2020-01-17
2018 Christopher A.G. Booth, Nikolaos Barkas, Wen Hao Neo, Hanane Boukarabila, Elizabeth J. Soilleux, George Giotopoulos, Noushin Farnoud, Alice Giustacchini, Neil Ashley, Joana Carrelha, Lauren Jamieson, Deborah Atkinson, Tiphaine Bouriez-Jones, Rab K. Prinjha, Thomas A. Milne, David T. Teachey, Elli Papaemmanuil, Brian J.P. Huntly, Sten Eirik W. Jacobsen, Adam J. Mead
Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors
published pages: 274-291.e8, ISSN: 1535-6108, DOI: 10.1016/j.ccell.2018.01.006
Cancer Cell 33/2 2020-01-17
2015 Louise van der Weyden, George Giotopoulos, Kim Wong, Alistair G. Rust, Carla Daniela Robles-Espinoza, Hikari Osaki, Brian J. Huntly, David J. Adams
Somatic drivers of B-ALL in a model of ETV6-RUNX1; Pax5 +/− leukemia
published pages: , ISSN: 1471-2407, DOI: 10.1186/s12885-015-1586-1
BMC Cancer 15/1 2020-01-17

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