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<p>Refractory cancers may arise either through the acquisition of resistance mechanisms or represent distinct disease states. The origin of childhood T-cell acute lymphoblastic leukaemia (T-ALL) that does not respond to initial treatment, i.e. refractory disease, is unknown. Refractory T-ALL carries a poor prognosis and cannot be predicted at diagnosis. Here, we perform single cell mRNA sequencing of T-ALL from 58 children (84 samples) who did, or did not respond to initial treatment. We identify a transcriptionally distinctive blast population, exhibiting features of innate-like lymphocytes, as the major source of refractory disease. Evidence of such blasts at diagnosis heralds refractory disease across independent datasets and is associated with survival in a large, contemporary trial cohort. Our findings portray refractory T-ALL as a distinct disease with the potential for immediate clinical utility.</p>

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A non-canonical lymphoblast in refractory childhood T-cell leukaemia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月12日

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  • Bram S. J. Lim,
  • Holly J. Whitfield,
  • Mi K. Trinh,
  • Gianna Bloye,
  • Rebecca Thomas,
  • Nathaniel D. Anderson,
  • Anna Wenger,
  • Angus Hodder,
  • Taryn D. Treger,
  • Henry Lee-Six,
  • Tim H. H. Coorens,
  • Conor Parks,
  • Toochi Ogbonnah,
  • Petri Pölönen,
  • Charles G. Mullighan,
  • David T. Teachey,
  • Jason Xu,
  • Kai Tan,
  • Melanie Hagleitner,
  • Lennart Kester,
  • Frank N. van Leeuwen,
  • Gordon Beattie,
  • Marc R. Mansour,
  • Owen Williams,
  • Jack Bartram,
  • Stuart Adams,
  • Laura Jardine,
  • Sam Behjati,
  • David O’Connor

摘要

Refractory cancers may arise either through the acquisition of resistance mechanisms or represent distinct disease states. The origin of childhood T-cell acute lymphoblastic leukaemia (T-ALL) that does not respond to initial treatment, i.e. refractory disease, is unknown. Refractory T-ALL carries a poor prognosis and cannot be predicted at diagnosis. Here, we perform single cell mRNA sequencing of T-ALL from 58 children (84 samples) who did, or did not respond to initial treatment. We identify a transcriptionally distinctive blast population, exhibiting features of innate-like lymphocytes, as the major source of refractory disease. Evidence of such blasts at diagnosis heralds refractory disease across independent datasets and is associated with survival in a large, contemporary trial cohort. Our findings portray refractory T-ALL as a distinct disease with the potential for immediate clinical utility.