Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A
Charlotte Brierley, Bon Ham Yip, Giulia Orlando, Jeremy Q. Wen, Sean Wen, Harsh Goyal, Max F. Levine, G. Maria Jakobsdottir, Avraam Tapinos, Alex J. Cornish, Antonio Rodriguez-Romera, Alba Rodríguez-Meira, Matthew Bashton, Angela Hamblin, Sally‐Ann Clark, Joseph C. Hamley, Olivia Fox, Mădălina Giurgiu, Jennifer O’Sullivan, Lauren C. Murphy, Assunta Adamo, Aude-Anaïs Olijnik, Anitria Cotton, Emily Hendrix, Shilpa Narina, Shondra M. Pruett‐Miller, Amir Enshaei, Claire Harrison, Mark W. Drummond, Steven Knapper, Ayalew Tefferi, Iléana Antony‐Debré, James Davies, Anton G. Henssen, Supat Thongjuea, David C. Wedge, Stefan N. Constantinescu, Elli Papaemmanuil, Bethan Psaila, John D. Crispino, Adam J. Mead
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.