2. Academic Validation
  3. Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A

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

  • Nat Genet. 2025 Jun;57(6):1478-1492. doi: 10.1038/s41588-025-02190-6.
Charlotte K Brierley # 1 2 3,  Bon Ham Yip # 4,  Giulia Orlando # 5,  Jeremy Wen 4,  Sean Wen 5,  Harsh Goyal 6 7 8 9,  Max Levine 10,  G Maria Jakobsdottir 11 12,  Avraam Tapinos 11 12,  Alex J Cornish 13,  Antonio Rodriguez-Romera 5,  Alba Rodriguez-Meira 5 14 15,  Matthew Bashton 16,  Angela Hamblin 17,  Sally Ann Clark 5,  Joseph C Hamley 5,  Olivia Fox 18,  Madalina Giurgiu 19 20,  Jennifer O'Sullivan 5 21,  Lauren Murphy 5,  Assunta Adamo 5,  Aude Anais Olijnik 5,  Anitria Cotton 4,  Emily Hendrix 22 23,  Shilpa Narina 22 23,  Shondra M Pruett-Miller 22 23,  Amir Enshaei 24,  Claire Harrison 21,  Mark Drummond 25,  Steven Knapper 26,  Ayalew Tefferi 27,  Iléana Antony-Debré 28 29 30,  James Davies 5,  Anton G Henssen 19 20,  Supat Thongjuea 5,  David C Wedge 11 12,  Stefan N Constantinescu 6 7 8 9,  Elli Papaemmanuil 31 10,  Bethan Psaila 5 17 9,  John D Crispino 32,  Adam J Mead 33 34
Affiliations

Affiliations

  • 1 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.
  • 2 Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. charlotte.brierley@imm.ox.ac.uk.
  • 3 Department of Haematology, OUH NHS Foundation Trust, Oxford, UK. charlotte.brierley@imm.ox.ac.uk.
  • 4 Division of Experimental Haematology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 5 Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM) and NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
  • 6 Ludwig Institute for Cancer Research Brussels, Brussels, Belgium.
  • 7 de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
  • 8 Walloon Excellence in Life Sciences and Biotechnology (WELBIO) Department, WEL Research Institute, Wavre, Belgium.
  • 9 Ludwig Institute for Cancer Research, Nuffield Department of Medicine, Oxford University, Oxford, UK.
  • 10 Isabl Inc., New York, NY, USA.
  • 11 Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
  • 12 Christie Hospital, The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
  • 13 Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
  • 14 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 15 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 16 The Hub for Biotechnology in the Built Environment, Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, UK.
  • 17 Department of Haematology, OUH NHS Foundation Trust, Oxford, UK.
  • 18 Oxford Regional Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
  • 19 Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • 20 Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin, Berlin, Germany.
  • 21 Department of Haematology, Guys and St Thomas' NHS Foundation Trust, London, UK.
  • 22 Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 23 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 24 Wolfson Childhood Cancer Research Centre, Newcastle University, Newcastle upon Tyne, UK.
  • 25 Department of Haematology, Beatson West of Scotland Cancer Centre, Glasgow, UK.
  • 26 Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, UK.
  • 27 Division of Hematology, Mayo Clinic, Rochester, MN, USA.
  • 28 INSERM, UMR 1287, Villejuif, France.
  • 29 Gustave Roussy, Villejuif, France.
  • 30 Université Paris Saclay, Gif-sur-Yvette, France.
  • 31 Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 32 Division of Experimental Haematology, St Jude Children's Research Hospital, Memphis, TN, USA. john.crispino@stjude.org.
  • 33 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.
  • 34 Department of Haematology, OUH NHS Foundation Trust, Oxford, UK. adam.mead@imm.ox.ac.uk.
  • # Contributed equally.
PMID: 40490510 DOI: 10.1038/s41588-025-02190-6
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.

Figures
Products