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<p>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. <i>DYRK1A</i>, 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. <i>DYRK1A</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月9日

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  • Charlotte K. 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

摘要

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.