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[Preprint]. 2023 Dec 10:2023.12.08.570880.
doi: 10.1101/2023.12.08.570880.

Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A

C K Brierley, B H Yip, G Orlando, H Goyal, S Wen, J Wen, M F Levine, G M Jakobsdottir, A Rodriguez-Meira, A Adamo, M Bashton, A Hamblin, S A Clark, J O'Sullivan, L Murphy, A A Olijnik, A Cotton, S Narina, S M Pruett-Miller, A Enshaei, C Harrison, M Drummond, S Knapper, A Tefferi, I Antony-Debré, S Thongjuea, D C Wedge, S Constantinescu, E Papaemmanuil, B Psaila, J D Crispino, A J Mead

Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A

C K Brierley et al. bioRxiv. .

Update in

  • Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A.
    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-Debré I, Davies J, Henssen AG, Thongjuea S, Wedge DC, Constantinescu SN, Papaemmanuil E, Psaila B, Crispino JD, Mead AJ. Brierley CK, et al. Nat Genet. 2025 Jun;57(6):1478-1492. doi: 10.1038/s41588-025-02190-6. Epub 2025 Jun 9. Nat Genet. 2025. PMID: 40490510 Free PMC article.

Abstract

Chromothripsis, the process of catastrophic shattering and haphazard repair of chromosomes, is a common event in cancer. Whether chromothripsis might constitute an actionable molecular event amenable to therapeutic targeting remains an open question. We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in ∼25% of patients ('chr21amp'). We report that chr21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. The chr21amp event is highly clonal and present throughout the hematopoietic hierarchy. DYRK1A , a serine threonine kinase and transcription factor, is the only gene in the 2.7Mb minimally amplified region which showed both increased expression and chromatin accessibility compared to non-chr21amp BP-MPN controls. We demonstrate that DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development, including DNA repair, STAT signalling and BCL2 overexpression. DYRK1A is essential for BP-MPN cell proliferation in vitro and in vivo , and DYRK1A inhibition synergises with BCL2 targeting to induce BP-MPN cell apoptosis. Collectively, these findings define the chr21amp event as a prognostic biomarker in BP-MPN and link chromothripsis to a druggable target.

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