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Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A

Brierley, C. K.
; 
Yip, B. H.
; 
Orlando, G.
; 
Wen, J.
; 
Wen, S.
; 
Goyal, H.
; 
Levine, M.
; 
Jakobsdottir, G. M.
; 
Tapinos, A.
; 
Cornish, A. J.
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Abstract
Chromothripsis, the chaotic shattering and repair of chromosomes, is common in cancer. Whether chromothripsis generates actionable therapeutic targets remains an open question. In a cohort of 64 patients in blast phase of a myeloproliferative neoplasm (BP-MPN), we describe recurrent amplification of a region of chromosome 21q ('chr. 21amp') in 25%, driven by chromothripsis in a third of these cases. We report that chr. 21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. DYRK1A, a serine threonine kinase, is the only gene in the 2.7-megabase minimally amplified region that showed both increased expression and chromatin accessibility compared with non-chr. 21amp BP-MPN controls. DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development and is essential for BP-MPN cell proliferation in vitro and in vivo, and represents a druggable axis. Collectively, these findings define chr. 21amp as a prognostic biomarker in BP-MPN, and link chromothripsis to a therapeutic target.
Authors
Brierley, C. K.
Yip, B. H.
Orlando, G.
Wen, J.
Wen, S.
Goyal, H.
Levine, M.
Jakobsdottir, G. M.
Tapinos, A.
Cornish, A. J.
Rodriguez-Romera, A.
Rodriguez-Meira, A.
Bashton, M.
Hamblin, A.
Clark, S. A.
Hamley, J. C.
Fox, O.
Giurgiu, M.
O'Sullivan, J.
Murphy, L.
Adamo, A.
Olijnik, A. A.
Cotton, A.
Hendrix, E.
Narina, S.
Pruett-Miller, S. M.
Enshaei, A.
Harrison, C.
Drummond, M.
Knapper, S.
Tefferi, A.
Antony-Debré, I.
Davies, J.
Henssen, A. G.
Thongjuea, S.
Wedge, D. C.
Constantinescu, S. N.
Papaemmanuil, E.
Psaila, B.
Crispino, J. D.
Mead, A. J.
Affiliation
Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM) and NIHR Biomedical Research Centre, University of Oxford, Oxford, UK. charlotte.brierley@imm.ox.ac.uk. Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. charlotte.brierley@imm.ox.ac.uk. Department of Haematology, OUH NHS Foundation Trust, Oxford, UK. charlotte.brierley@imm.ox.ac.uk. Division of Experimental Haematology, St Jude Children's Research Hospital, Memphis, TN, USA. Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM) and NIHR Biomedical Research Centre, University of Oxford, Oxford, UK. Ludwig Institute for Cancer Research Brussels, Brussels, Belgium. de Duve Institute, Université Catholique de Louvain, Brussels, Belgium. Walloon Excellence in Life Sciences and Biotechnology (WELBIO) Department, WEL Research Institute, Wavre, Belgium. Ludwig Institute for Cancer Research, Nuffield Department of Medicine, Oxford University, Oxford, UK. Isabl Inc., New York, NY, USA. Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Christie Hospital, The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. The Hub for Biotechnology in the Built Environment, Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, UK. Department of Haematology, OUH NHS Foundation Trust, Oxford, UK. Oxford Regional Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany. Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin, Berlin, Germany. Department of Haematology, Guys and St Thomas' NHS Foundation Trust, London, UK. Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, TN, USA. Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. Wolfson Childhood Cancer Research Centre, Newcastle University, Newcastle upon Tyne, UK. Department of Haematology, Beatson West of Scotland Cancer Centre, Glasgow, UK. Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, UK. Division of Hematology, Mayo Clinic, Rochester, MN, USA. INSERM, UMR 1287, Villejuif, France. Gustave Roussy, Villejuif, France. Université Paris Saclay, Gif-sur-Yvette, France. Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Division of Experimental Haematology, St Jude Children's Research Hospital, Memphis, TN, USA. john.crispino@stjude.org. Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM) and NIHR Biomedical Research Centre, University of Oxford, Oxford, UK. adam.mead@imm.ox.ac.uk. Department of Haematology, OUH NHS Foundation Trust, Oxford, UK. adam.mead@imm.ox.ac.uk.
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2025
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All Christie Publications
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Brierley CK, Yip BH, Orlando G, Wen J, Wen S, Goyal H, et al. Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A. Nature genetics. 2025 Jun;57(6):1478-92. PubMed PMID: 40490510. Pubmed Central PMCID: PMC12165854 Alethiomics Ltd, a spin out company from the University of Oxford with equity owned by B.P. and A.J.M. E.P. is a founder, equity holder and holds a fiduciary role in Isabl Inc. A.J.C. is an employee of Owkin UK Ltd. The other authors declare no competing interests. Epub 2025/06/10. eng.
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https://christie.openrepository.com/handle/10541/627579
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