TY - JOUR
T1 - Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A
AU - Brierley, Charlotte K
AU - Yip, Bon Ham
AU - Orlando, Giulia
AU - Wen, Jeremy
AU - Wen, Sean
AU - Goyal, Harsh
AU - Levine, Max
AU - Jakobsdottir, G Maria
AU - Tapinos, Avraam
AU - Cornish, Alex J
AU - Rodriguez-Romera, Antonio
AU - Rodriguez-Meira, Alba
AU - Bashton, Matthew
AU - Hamblin, Angela
AU - Clark, Sally Ann
AU - Hamley, Joseph C
AU - Fox, Olivia
AU - Giurgiu, Madalina
AU - O'Sullivan, Jennifer
AU - Murphy, Lauren
AU - Adamo, Assunta
AU - Olijnik, Aude Anais
AU - Cotton, Anitria
AU - Hendrix, Emily
AU - Narina, Shilpa
AU - Pruett-Miller, Shondra M
AU - Enshaei, Amir
AU - Harrison, Claire
AU - Drummond, Mark
AU - Knapper, Steven
AU - Tefferi, Ayalew
AU - Antony-Debré, Iléana
AU - Davies, James
AU - Henssen, Anton G
AU - Thongjuea, Supat
AU - Wedge, David C
AU - Constantinescu, Stefan N
AU - Papaemmanuil, Elli
AU - Psaila, Bethan
AU - Crispino, John D
AU - Mead, Adam J
N1 - © 2025. The Author(s).
PY - 2025/6
Y1 - 2025/6
N2 - 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.
AB - 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.
KW - Humans
KW - Dyrk Kinases
KW - Protein Serine-Threonine Kinases/genetics
KW - Protein-Tyrosine Kinases/genetics
KW - Chromothripsis
KW - Chromosomes, Human, Pair 21/genetics
KW - Myeloproliferative Disorders/genetics
KW - Female
KW - Male
KW - Blast Crisis/genetics
KW - Cell Transformation, Neoplastic/genetics
KW - Gene Amplification
KW - Middle Aged
KW - Cell Proliferation/genetics
KW - Animals
KW - Mice
U2 - 10.1038/s41588-025-02190-6
DO - 10.1038/s41588-025-02190-6
M3 - Article
C2 - 40490510
SN - 1061-4036
VL - 57
SP - 1478
EP - 1492
JO - Nature Genetics
JF - Nature Genetics
IS - 6
ER -
