Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A.
(2025) Nature Genetics — Vol. 57, n° 6, p. 1478-1492 (2025)
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Brierley, Charlotte K 
Mead, Adam J
- 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.
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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., et al. (2025). Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A. Nature Genetics, 57(6), 1478-1492. https://doi.org/10.1038/s41588-025-02190-6 (Original work published 2025)