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<p>Circular RNAs (circRNAs) are increasingly recognized as functional non-coding transcripts with oncogenic potential. Here, a comprehensive analysis of circRNA expression in primary ALK(+) anaplastic large-cell lymphoma (ALK(<b> + </b>) ALCL) is presented. Integrated transcriptomic profiling revealed that aberrant expression of circZBTB46 and of its linear host transcript, normally restricted to dendritic cells, is exclusive to ALK(+) lymphoma cells and driven by the oncogenic NPM1::ALK/STAT3 axis. Functional studies showed that circZBTB46, unlike its protein-coding counterpart, promotes resistance to the ALK inhibitor crizotinib. Silencing circZBTB46 restored crizotinib sensitivity in resistant ALCL cells both in vitro and in vivo. Transcriptomic analyses identified PIP5K1C as a downstream effector regulated through a competitive endogenous RNA mechanism in which circZBTB46 acts as a sponge to miR-25-3p, alleviating its repression of PIP5K1C. These findings uncover a previously unrecognized mechanism of drug resistance in ALK(<b> + </b>) ALCL and establish circZBTB46 as a promising therapeutic target.</p><p></p>

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CircZBTB46, a promising therapeutic target in crizotinib resistant ALK-positive T lymphomas

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月26日

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  • Loélia Babin,
  • Elissa Andraos,
  • Steffen Fuchs,
  • Chloe Bessière,
  • Lola Colras,
  • Sandra Dailhau,
  • Cathy Quelen,
  • Cindy Pinto,
  • Iyad Daoudi,
  • Romain Pfeifer,
  • Ahmed Zamani,
  • Marina Bousquet,
  • Stéphane Pyronnet,
  • Christine Gaspin,
  • Laurence Lamant,
  • Fabienne Meggetto

摘要

Circular RNAs (circRNAs) are increasingly recognized as functional non-coding transcripts with oncogenic potential. Here, a comprehensive analysis of circRNA expression in primary ALK(+) anaplastic large-cell lymphoma (ALK( + ) ALCL) is presented. Integrated transcriptomic profiling revealed that aberrant expression of circZBTB46 and of its linear host transcript, normally restricted to dendritic cells, is exclusive to ALK(+) lymphoma cells and driven by the oncogenic NPM1::ALK/STAT3 axis. Functional studies showed that circZBTB46, unlike its protein-coding counterpart, promotes resistance to the ALK inhibitor crizotinib. Silencing circZBTB46 restored crizotinib sensitivity in resistant ALCL cells both in vitro and in vivo. Transcriptomic analyses identified PIP5K1C as a downstream effector regulated through a competitive endogenous RNA mechanism in which circZBTB46 acts as a sponge to miR-25-3p, alleviating its repression of PIP5K1C. These findings uncover a previously unrecognized mechanism of drug resistance in ALK( + ) ALCL and establish circZBTB46 as a promising therapeutic target.