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<p>Cytogenetic and genomic profiling of acute myeloid leukemia (AML) guides personalized treatment according to ELN2022 recommendations. However, marked outcome variability persists among cytogenetically normal (CN-) patients, representing an unmet clinical need. We used long-read whole-genome sequencing to interrogate the prognostic significance of structural variations (SVs) in a prospective cohort of 162 intensively treated CN-AML patients. After stringent filtering, we identified 5 somatic SVs associated with shorter overall survival (OS) (HR:4.18, p &lt; 0.001) and event-free survival (EFS) (HR:3.59, p &lt; 0.001) in 13% of the patients. Results were validated in a real-world cohort of 149 CN-AML, using target assays. These high-risk SVs (HRVs) operationally defined a “very high-risk” category in the framework of ELN2022, overall resulting in more accurate OS prediction. HRVs were independent of most frequent mutations, particularly <i>FLT3</i><sup>ITD</sup> and <i>NPM1</i><sup>mut</sup>. Among the latter patients, HRVs independently predicted shorter OS (8.2 months versus not-reached; p &lt; 0.001), EFS (3.5 versus 25.7 months; p &lt; 0.001), and lower complete response rates (66.7% versus 90.1%; p &lt; 0.005). Finally, we provided evidence of transcriptional deregulation of SV-related genes in primary samples and engineered cell models. Current findings support the value of SVs for refining risk stratification in CN-AML, by identifying patients at exceedingly dismal outcome who might benefit from personalized approaches.</p>

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Genomic structural variations contribute to inform prognosis in patients with cytogenetically normal acute myeloid leukemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月6日

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  • Niccolò Bartalucci,
  • Francesco Mannelli,
  • Danilo Tarantino,
  • Alessio Enderti,
  • Simone Romagnoli,
  • Daniele Colazzo,
  • Barbara Scappini,
  • Giacomo Gianfaldoni,
  • Matteo Piccini,
  • Leonardo Signori,
  • Fiorenza Irushani,
  • Silvia Salmoiraghi,
  • Tiziana Ottone,
  • Alfonso Piciocchi,
  • Margherita Vannucchi,
  • Maria Chiara Siciliano,
  • Roberto Boccacci,
  • Silvia Orsi,
  • Alessia Civini,
  • Paola Fazi,
  • Raffaella Santi,
  • Marco Vignetti,
  • Stefania Bortoluzzi,
  • Alberto Bosi,
  • Adriano Venditti,
  • Alessandro Rambaldi,
  • Maria Teresa Voso,
  • Paola Guglielmelli,
  • Alessandro M. Vannucchi

摘要

Cytogenetic and genomic profiling of acute myeloid leukemia (AML) guides personalized treatment according to ELN2022 recommendations. However, marked outcome variability persists among cytogenetically normal (CN-) patients, representing an unmet clinical need. We used long-read whole-genome sequencing to interrogate the prognostic significance of structural variations (SVs) in a prospective cohort of 162 intensively treated CN-AML patients. After stringent filtering, we identified 5 somatic SVs associated with shorter overall survival (OS) (HR:4.18, p < 0.001) and event-free survival (EFS) (HR:3.59, p < 0.001) in 13% of the patients. Results were validated in a real-world cohort of 149 CN-AML, using target assays. These high-risk SVs (HRVs) operationally defined a “very high-risk” category in the framework of ELN2022, overall resulting in more accurate OS prediction. HRVs were independent of most frequent mutations, particularly FLT3ITD and NPM1mut. Among the latter patients, HRVs independently predicted shorter OS (8.2 months versus not-reached; p < 0.001), EFS (3.5 versus 25.7 months; p < 0.001), and lower complete response rates (66.7% versus 90.1%; p < 0.005). Finally, we provided evidence of transcriptional deregulation of SV-related genes in primary samples and engineered cell models. Current findings support the value of SVs for refining risk stratification in CN-AML, by identifying patients at exceedingly dismal outcome who might benefit from personalized approaches.