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COMAL SIGNED

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

Total Cost €

EC-Contrib. €

Partnership

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Outcomes and
results

COMAL project word cloud

Explore the words cloud of the COMAL project. It provides you a very rough idea of what is the project "COMAL" about.

function mutated enhancer suggests vivo patients mediated disease therapies mutations silac model hi cell exemplar hematopoiesis mechanisms genomic suggest aml proteomics roles segregation acute leukemia characterisation inform dyregulation compounds techniques chip biology dna capture data survival communication underlie promoters myeloid chromosomal binding aggressive seq vulnerabilities generation rate outcomes 15 repair models transcriptional normal chromosome screen samples insulator lines rna cells chromatid obj co patient mutant proper candidate cohesin regulation members alteration therapeutic demonstrated cancer leukaemia mouse urgently cohesion transformation suggested alterations dismal sister defects driver mediates tested 30 preliminary altered lt

Project "COMAL" data sheet

The following table provides information about the project.

Coordinator	THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE Organization address address: TRINITY LANE THE OLD SCHOOLS city: CAMBRIDGE postcode: CB2 1TN website: www.cam.ac.uk 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

Partnership

Take a look of project's partnership.

#	participants	country	role	EC contrib. [€]
1	THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE Organization address address: TRINITY LANE THE OLD SCHOOLS city: CAMBRIDGE postcode: CB2 1TN website: www.cam.ac.uk contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.	UK (CAMBRIDGE)	coordinator	1˙999˙574.00

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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.

Objectives:

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

Publications

List of publications.
year	authors and title	journal	last update
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 GÃ¶ttgens, 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 DÃ¶hner, 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 GÃ¶ttgens, 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, JoÃ£o 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 DeÂ Braekeleer, Yilong Li, Emmanouil Metzakopian, OliverÂ M. Dovey, Annalisa Mupo, Vera Grinkevich, Meng Li, Milena Mazan, Malgorzata Gozdecka, Shuhei Ohnishi, Jonathan Cooper, Miten Patel, Thomas McKerrell, Bin Chen, AnaÂ Filipa Domingues, Paolo Gallipoli, Sarah Teichmann, Hannes Ponstingl, Ultan McDermott, Julio Saez-Rodriguez, BrianÂ J.P. Huntly, Francesco Iorio, Cristina Pina, GeorgeÂ 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, AyÅŸegÃ¼l 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	NeilÂ A. Barrett, Camille Malouf, Chrysa Kapeni, WendiÂ A. Bacon, George Giotopoulos, StenÂ EirikÂ W. Jacobsen, BrianÂ 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 GonÃ§alves, 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 WÃ¶rmann, T BÃ¼chner, 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 +/âˆ’ leukemia published pages: , ISSN: 1471-2407, DOI: 10.1186/s12885-015-1586-1	BMC Cancer 15/1	2020-01-17

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