Journal article
Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 8.2MB, Terms of use)
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(Supplementary materials, zip, 809.6KB, Terms of use)
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- Publisher copy:
- 10.1038/s41588-025-02190-6
Authors
+ Leukaemia UK
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- Funder identifier:
- https://ror.org/00xsz4758
- Grant:
- 2021/JGF/005
- Programme:
- John Goldman Fellowship
+ University of Oxford
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- Funder identifier:
- https://ror.org/052gg0110
- Grant:
- 101/517
- 131/030
- Programme:
- John Fell Fund
+ Wellcome Trust
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- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- 222800/Z/21/Z
- 203141/Z/16/Z
- 220586/Z/20/Z
+ Cancer Research UK
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- Funder identifier:
- https://ror.org/054225q67
- Grant:
- RCCSCF-May24/100001
- CTRQQR-2021\100002
- C67633/ A29034
- C42639/A26988
+ National Institute for Health and Care Research
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- Funder identifier:
- https://ror.org/0187kwz08
- Grant:
- NIHR203308
- Publisher:
- Springer Nature
- Journal:
- Nature Genetics More from this journal
- Volume:
- 57
- Issue:
- 6
- Pages:
- 1478–1492
- Publication date:
- 2025-06-09
- Acceptance date:
- 2025-04-08
- DOI:
- EISSN:
-
1546-1718
- ISSN:
-
1061-4036
- Language:
-
English
- Pubs id:
-
2129078
- Local pid:
-
pubs:2129078
- Deposit date:
-
2025-06-10
- ARK identifier:
Terms of use
- Copyright holder:
- Brierley et al.
- Copyright date:
- 2025
- Rights statement:
- © The Author(s) 2025. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
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