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| Item Type: | Article |
|---|---|
| Title: | Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A |
| Creators: |
Brierley, C.K.  ORCID: https://orcid.org/0000-0002-4028-3733, Yip, B.H., Orlando, G., Wen, J., Wen, S., Goyal, H., Levine, M. ORCID: https://orcid.org/0000-0001-5156-9086, Jakobsdottir, G.M. ORCID: https://orcid.org/0000-0001-8225-6541, Tapinos, A., Cornish, A.J. ORCID: https://orcid.org/0000-0002-3966-3501, Rodriguez-Romera, A. ORCID: https://orcid.org/0000-0001-7193-9144, Rodriguez-Meira, A., Bashton, M., Hamblin, A., Clark, S.A., Hamley, J.C., Fox, O., Giurgiu, M. ORCID: https://orcid.org/0000-0001-5007-7442, O'Sullivan, J., Murphy, L., Adamo, A., Olijnik, A.A. ORCID: https://orcid.org/0000-0002-0980-6663, Cotton, A., Hendrix, E. ORCID: https://orcid.org/0009-0006-0514-3918, Narina, S. ORCID: https://orcid.org/0000-0002-9952-1302, Pruett-Miller, S.M. ORCID: https://orcid.org/0000-0002-3793-585X, Enshaei, A. ORCID: https://orcid.org/0000-0002-7464-0743, Harrison, C. ORCID: https://orcid.org/0000-0002-3212-920X, Drummond, M., Knapper, S., Tefferi, A., Antony-Debré, I. ORCID: https://orcid.org/0000-0002-1911-146X, Davies, J. ORCID: https://orcid.org/0000-0002-4108-4357, Henssen, A.G. ORCID: https://orcid.org/0000-0003-1534-778X, Thongjuea, S., Wedge, D.C. ORCID: https://orcid.org/0000-0002-7572-3196, Constantinescu, S.N., Papaemmanuil, E. ORCID: https://orcid.org/0000-0003-1709-8983, Psaila, B. ORCID: https://orcid.org/0000-0001-8198-9663, Crispino, J.D. ORCID: https://orcid.org/0000-0002-8182-8306 and Mead, A.J. ORCID: https://orcid.org/0000-0001-8522-1002
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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. |
| Keywords: | Blast Crisis, Cell Proliferation, Chromothripsis, Dyrk Kinases, Gene Amplification, Myeloproliferative Disorders, Neoplastic Cell Transformation, Pair 21 Human Chromosomes, Protein Serine-Threonine Kinases, Protein-Tyrosine Kinases, Animals, Mice |
| Source: | Nature Genetics |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Volume: | 57 |
| Number: | 6 |
| Page Range: | 1478-1492 |
| Date: | June 2025 |
| Official Publication: | https://doi.org/10.1038/s41588-025-02190-6 |
| PubMed: | View item in PubMed |
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