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

Brierley, Charlotte K., Yip, Bon Ham, Orlando, Giulia, Wen, Jeremy, Wen, Sean, Goyal, Harsh, Levine, Max, Jakobsdottir, G. Maria, Tapinos, Avraam, Cornish, Alex J., Rodriguez-Romera, Antonio, Rodriguez-Meira, Alba, Bashton, Matthew, Hamblin, Angela, Clark, Sally Ann, Hamley, Joseph C., Fox, Olivia, Giurgiu, Madalina, O’Sullivan, Jennifer, Murphy, Lauren, Adamo, Assunta, Olijnik, Aude Anais, Cotton, Anitria, Hendrix, Emily, Narina, Shilpa, Pruett-Miller, Shondra M., Enshaei, Amir, Harrison, Claire, Drummond, Mark, Knapper, Steven ORCID: https://orcid.org/0000-0002-6405-4441, Tefferi, Ayalew, Antony-Debré, Iléana, Davies, James, Henssen, Anton G., Thongjuea, Supat, Wedge, David C., Constantinescu, Stefan N., Papaemmanuil, Elli, Psaila, Bethan, Crispino, John D. and Mead, Adam J. 2025. Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A. Nature Genetics 57 (6) , pp. 1478-1492. 10.1038/s41588-025-02190-6

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
ISSN:	1061-4036
Date of First Compliant Deposit:	18 June 2025
Date of Acceptance:	8 April 2025
Last Modified:	18 Jun 2025 09:45
URI:	https://orca.cardiff.ac.uk/id/eprint/179149

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