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

   

Authors:	Brierley, C. K.; Yip, B. H.; Orlando, G.; Wen, J.; Wen, S.; Goyal, H.; Levine, M.; Jakobsdottir, G. M.; Tapinos, A.; Cornish, A. J.; Rodriguez-Romera, A.; Rodriguez-Meira, A.; Bashton, M.; Hamblin, A.; Clark, S. A.; Hamley, J. C.; Fox, O.; Giurgiu, M.; O’Sullivan, J.; Murphy, L.; Adamo, A.; Olijnik, A. A.; Cotton, A.; Hendrix, E.; Narina, S.; Pruett-Miller, S. M.; Enshaei, A.; Harrison, C.; Drummond, M.; Knapper, S.; Tefferi, A.; Antony-Debré, I.; Davies, J.; Henssen, A. G.; Thongjuea, S.; Wedge, D. C.; Constantinescu, S. N.; Papaemmanuil, E.; Psaila, B.; Crispino, J. D.; Mead, A. J.
Article Title:	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. © The Author(s) 2025.
Keywords:	middle aged; myeloproliferative disorders; genetics; myeloproliferative disorder; cell proliferation; mouse; animal; metabolism; animals; mice; gene amplification; pathology; protein serine threonine kinase; protein tyrosine kinase; cell transformation, neoplastic; protein-tyrosine kinases; chromosome 21; chromosomes, human, pair 21; blast cell crisis; blast crisis; chromothripsis; humans; human; male; female; protein serine-threonine kinases; neoplastic cell transformation; dyrk kinases; dyrk kinase
Journal Title:	Nature Genetics
Volume:	57
Issue:	6
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Date Published:	2025-06-01
Start Page:	1478
End Page:	1492
Language:	English
DOI:	10.1038/s41588-025-02190-6
PUBMED:	40490510
PROVIDER:	scopus
PMCID:	PMC12165854
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105007610566&doi=10.1038%2fs41588-025-02190-6&partnerID=40&md5=64a635f5a284b4ab29b6d506cb453131
Notes:	Article -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/226330