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

BABIN, L.; Andraos, E.; Fuchs, S.; Bessiere, C.; Colras, L.; Quelen, C.; Pinto, C.; Daoudi, I.; Pfeifer, R.; Zamani, A.; Bousquet, M.; Pyronnet, S.; Gaspin, C.; Lamant, L.; Meggetto, F.

doi:10.64898/2026.01.13.699235

bioRxiv · 10.64898/2026.01.13.699235

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

BABIN, L.·Andraos, E.·Fuchs, S.·Bessiere, C.·Colras, L.·Quelen, C.·Pinto, C.·Daoudi, I.·Pfeifer, R.·Zamani, A.·Bousquet, M.·Pyronnet, S.·Gaspin, C.·Lamant, L.·Meggetto, F.

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Abstract

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.

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BABIN, L., Andraos, E., Fuchs, S., Bessiere, C., Colras, L., Quelen, C., Pinto, C., Daoudi, I., Pfeifer, R., Zamani, A., Bousquet, M., Pyronnet, S., Gaspin, C., Lamant, L., Meggetto, F.. 2026-01-14. CircZBTB46, a promising therapeutic target in crizotinib resistant ALK-positive T lymphomas. https://doi.org/10.64898/2026.01.13.699235

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