Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A PMID: 40490510

ADC Targets in Oncology

2026-04-10

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

1. Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM) and NIHR Biomedical Research Centre, University of Oxford, Oxford, UK. [email protected].
2. Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
3. Department of Haematology, OUH NHS Foundation Trust, Oxford, UK. [email protected].
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. [email protected].
33. Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM) and NIHR Biomedical Research Centre, University of Oxford, Oxford, UK. [email protected].
34. Department of Haematology, OUH NHS Foundation Trust, Oxford, UK. [email protected].
# Contributed equally.

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.