2025-06-11 オックスフォード大学
<関連情報>
- https://www.ox.ac.uk/news/2025-06-11-oxford-researchers-uncover-potential-new-therapeutic-target-hard-treat-form
- https://www.nature.com/articles/s41588-025-02190-6
染色体不連続症に伴う21番染色体の増幅が、DYRK1Aの標的化可能な過剰発現を介して、芽球相MPNへの形質転換を制御する Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A
Charlotte K. Brierley,Bon Ham Yip,Giulia Orlando,Jeremy Wen,Sean Wen,Harsh Goyal,Max Levine,G. Maria Jakobsdottir,Avraam Tapinos,Alex J. Cornish,Antonio Rodriguez-Romera,Alba Rodriguez-Meira,Matthew Bashton,Angela Hamblin,Sally Ann Clark,Joseph C. Hamley,Olivia Fox,Madalina Giurgiu,Jennifer O’Sullivan,Lauren Murphy,Assunta Adamo,Aude Anais Olijnik,Anitria Cotton,Emily Hendrix,… Adam J. Mead
Nature Genetics Published:09 June 2025
DOI:https://doi.org/10.1038/s41588-025-02190-6
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.
