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

Charlotte Katharina Brierley; Bon Ham Yip; Giulia Orlando; Jeremy Wen; Sean Wen; Harsh Goyal; Max Levine; G. Maria Jakobsdottir; Avraam Tapinos; Alex J. Cornish; Antonio Rodriguez-Romera; Alba Rodriguez-Meira; Matthew Bashton; Angela Hamblin; Sally Ann Clark; Joseph C. Hamley; Olivia Fox; Madalina Giurgiu; Jennifer O’Sullivan; Lauren Murphy; Assunta Adamo; Aude Anais Olijnik; Anitria Cotton; Emily Hendrix; Shilpa Narina; Shondra M. Pruett-Miller; Amir Enshaei; Claire Harrison; Mark 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

doi:10.1038/s41588-025-02190-6

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

Charlotte Katharina Brierley^*, Bon Ham Yip, Giulia Orlando, Jeremy Wen, Sean Wen, Harsh Goyal, Max Levine, G. Maria Jakobsdottir, Avraam Tapinos, Alex J. Cornish, Antonio Rodriguez-Romera, Alba Rodriguez-Meira, Matthew Bashton, Angela Hamblin, Sally Ann Clark, Joseph C. Hamley, Olivia Fox, Madalina Giurgiu, Jennifer O’Sullivan, Lauren MurphyAssunta Adamo, Aude Anais Olijnik, Anitria Cotton, Emily Hendrix, Shilpa Narina, Shondra M. Pruett-Miller, Amir Enshaei, Claire Harrison, Mark 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^*

^*Corresponding author for this work

Applied Sciences Department

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1478-1492
Number of pages	15
Journal	Nature Genetics
Volume	57
Issue number	6
Early online date	9 Jun 2025
DOIs	https://doi.org/10.1038/s41588-025-02190-6
Publication status	Published - Jun 2025

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Cite this

Brierley, C. K., Yip, B. H., Orlando, G., Wen, J., Wen, S., Goyal, H., Levine, M., Jakobsdottir, G. M., Tapinos, A., Cornish, A. J., Rodriguez-Romera, A., Rodriguez-Meira, A., Bashton, M., Hamblin, A., Clark, S. A., Hamley, J. C., Fox, O., Giurgiu, M., O’Sullivan, J., ... Mead, A. J. (2025). Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A. Nature Genetics, 57(6), 1478-1492. https://doi.org/10.1038/s41588-025-02190-6

@article{a59aede9d97944718f0bfb5afb956766,

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

abstract = "Chromothripsis, the chaotic shattering and repair of chromosomes,is common in cancer. Whether chromothripsis generates actionabletherapeutic targets remains an open question. In a cohort of 64 patientsin blast phase of a myeloproliferative neoplasm (BP-MPN), we describerecurrent amplification of a region of chromosome 21q ({\textquoteleft}chr. 21amp{\textquoteright}) in 25%,driven by chromothripsis in a third of these cases. We report that chr. 21ampBP-MPN has a particularly aggressive and treatment-resistant phenotype.DYRK1A, a serine threonine kinase, is the only gene in the 2.7-megabaseminimally amplified region that showed both increased expression andchromatin accessibility compared with non-chr. 21amp BP-MPN controls.DYRK1A is a central node at the nexus of multiple cellular functions criticalfor BP-MPN development and is essential for BP-MPN cell proliferationin vitro and in vivo, and represents a druggable axis. Collectively, thesefindings define chr. 21amp as a prognostic biomarker in BP-MPN, and linkchromothripsis to a therapeutic target.",

author = "Brierley, {Charlotte Katharina} and Yip, {Bon Ham} and Giulia Orlando and Jeremy Wen and Sean Wen and Harsh Goyal and Max Levine and Jakobsdottir, {G. Maria} and Avraam Tapinos and Cornish, {Alex J.} and Antonio Rodriguez-Romera and Alba Rodriguez-Meira and Matthew Bashton and Angela Hamblin and Clark, {Sally Ann} and Hamley, {Joseph C.} and Olivia Fox and Madalina Giurgiu and Jennifer O{\textquoteright}Sullivan and Lauren Murphy and Assunta Adamo and Olijnik, {Aude Anais} and Anitria Cotton and Emily Hendrix and Shilpa Narina and Pruett-Miller, {Shondra M.} and Amir Enshaei and Claire Harrison and Mark Drummond and Steven Knapper and Ayalew Tefferi and Il{\'e}ana Antony-Debr{\'e} and James Davies and Henssen, {Anton G.} and Supat Thongjuea and Wedge, {David C.} and Constantinescu, {Stefan N.} and Elli Papaemmanuil and Bethan Psaila and Crispino, {John D.} and Mead, {Adam J.}",

year = "2025",

month = jun,

doi = "10.1038/s41588-025-02190-6",

language = "English",

volume = "57",

pages = "1478--1492",

journal = "Nature Genetics",

issn = "1061-4036",

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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 2025, 'Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A', Nature Genetics, vol. 57, no. 6, pp. 1478-1492. https://doi.org/10.1038/s41588-025-02190-6

TY - JOUR

T1 - Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A

AU - Brierley, Charlotte Katharina

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.

PY - 2025/6

Y1 - 2025/6

N2 - Chromothripsis, the chaotic shattering and repair of chromosomes,is common in cancer. Whether chromothripsis generates actionabletherapeutic targets remains an open question. In a cohort of 64 patientsin blast phase of a myeloproliferative neoplasm (BP-MPN), we describerecurrent amplification of a region of chromosome 21q (‘chr. 21amp’) in 25%,driven by chromothripsis in a third of these cases. We report that chr. 21ampBP-MPN has a particularly aggressive and treatment-resistant phenotype.DYRK1A, a serine threonine kinase, is the only gene in the 2.7-megabaseminimally amplified region that showed both increased expression andchromatin accessibility compared with non-chr. 21amp BP-MPN controls.DYRK1A is a central node at the nexus of multiple cellular functions criticalfor BP-MPN development and is essential for BP-MPN cell proliferationin vitro and in vivo, and represents a druggable axis. Collectively, thesefindings define chr. 21amp as a prognostic biomarker in BP-MPN, and linkchromothripsis to a therapeutic target.

AB - Chromothripsis, the chaotic shattering and repair of chromosomes,is common in cancer. Whether chromothripsis generates actionabletherapeutic targets remains an open question. In a cohort of 64 patientsin blast phase of a myeloproliferative neoplasm (BP-MPN), we describerecurrent amplification of a region of chromosome 21q (‘chr. 21amp’) in 25%,driven by chromothripsis in a third of these cases. We report that chr. 21ampBP-MPN has a particularly aggressive and treatment-resistant phenotype.DYRK1A, a serine threonine kinase, is the only gene in the 2.7-megabaseminimally amplified region that showed both increased expression andchromatin accessibility compared with non-chr. 21amp BP-MPN controls.DYRK1A is a central node at the nexus of multiple cellular functions criticalfor BP-MPN development and is essential for BP-MPN cell proliferationin vitro and in vivo, and represents a druggable axis. Collectively, thesefindings define chr. 21amp as a prognostic biomarker in BP-MPN, and linkchromothripsis to a therapeutic target.

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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 -

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

Abstract

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