CircZBTB46, a promising therapeutic target in crizotinib resistant ALK-positive T lymphomas
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.
Authors
- Christine Gaspin (ORCID: https://orcid.org/0000-0003-0304-5186)
- Laurence Lamant (ORCID: https://orcid.org/0000-0002-1123-7658)
- Fabienne Meggetto (ORCID: https://orcid.org/0000-0002-2610-0144)
- Steffen Fuchs (ORCID: https://orcid.org/0000-0001-9619-4329)
- Cathy Quelen (ORCID: https://orcid.org/0000-0003-0576-2234)
- Stéphane Pyronnet (ORCID: https://orcid.org/0000-0002-9562-5112)
- Chloé Bessière (ORCID: https://orcid.org/0000-0001-7518-3559)
- Marina Bousquet (ORCID: https://orcid.org/0000-0001-8333-1144)
- Elissa Andraos (ORCID: https://orcid.org/0000-0003-0630-3742)
- Sandra Dailhau
- Loélia Babin (ORCID: https://orcid.org/0000-0002-0188-6582)
- Romain Pfeifer
- Lola Colras
- Iyad Daoudi
- Ahmed Zamani
- Cindy Pinto
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Humboldt-Universität zu Berlin (DE)
- Centre de Recherches en Cancérologie de Toulouse (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Génétique Physiologie et Systèmes d'Elevage (FR)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Leukemia
- Published
- 2026-06-26
- DOI
- https://doi.org/10.1038/s41375-026-03018-w
- Primary Topic
- Circular RNAs in diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00