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.
Show 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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