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.
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.