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

Lookup NU author(s): Dr Matthew BashtonORCiD, Dr Amir EnshaeiORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© The Author(s) 2025. 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 metadata

Author(s): Brierley CK, Yip BH, Orlando G, Wen J, Wen S, Goyal H, Levine M, Jakobsdottir GM, Tapinos A, Cornish AJ, Rodriguez-Romera A, Rodriguez-Meira A, Bashton M, Hamblin A, Clark SA, Hamley JC, Fox O, Giurgiu M, O'Sullivan J, Murphy L, Adamo A, Olijnik AA, Cotton A, Hendrix E, Narina S, Pruett-Miller SM, Enshaei A, Harrison C, Drummond M, Knapper S, Tefferi A, Antony-Debre I, Davies J, Henssen AG, Thongjuea S, Wedge DC, Constantinescu SN, Papaemmanuil E, Psaila B, Crispino JD, Mead AJ

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2025

Volume: 57

Issue: 6

Pages: 1478-1492

Print publication date: 01/06/2025

Online publication date: 09/06/2025

Acceptance date: 08/04/2025

Date deposited: 26/06/2025

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41588-025-02190-6

DOI: 10.1038/s41588-025-02190-6

Data Access Statement: All raw and processed sequencing data generated in this study will be made publically available at the NCBI Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/) under accession numbers GSE228060 for CRISPR KO clones, GSE240407 for RNA/ATAC and GSE292030 for single-cell primary patient data. The TARGET-seq single-cell dataset is available in raw and processed format at GEO accession number GSE226340 and SRA accession number PRJNA930152. The raw and processed SNP array data and single-cell (10×) Seurat object generated in this manuscript are available via Zenodo at https://doi.org/10.5281/zenodo.14749739 (ref. 73). Whole genome sequencing data have been deposited at the European Genome-phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGAS00001007483. [See the article for the full data access statement.]

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