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Here, a comprehensive analysis of circRNA expression in primary ALK(+) anaplastic large-cell lymphoma (ALK(\n                    <jats:bold>\u2009+\u2009<\/jats:bold>\n                    ) 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(\n                    <jats:bold>\u2009+\u2009<\/jats:bold>\n                    ) ALCL and establish circZBTB46 as a promising therapeutic target.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-03018-w","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T13:28:26Z","timestamp":1782480506000},"page":"1735-1747","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CircZBTB46, a promising therapeutic target in crizotinib resistant ALK-positive T lymphomas"],"prefix":"10.1038","volume":"40","author":[{"given":"Lo\u00e9lia","family":"Babin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elissa","family":"Andraos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Fuchs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7518-3559","authenticated-orcid":false,"given":"Chloe","family":"Bessi\u00e8re","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lola","family":"Colras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5907-889X","authenticated-orcid":false,"given":"Sandra","family":"Dailhau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0576-2234","authenticated-orcid":false,"given":"Cathy","family":"Quelen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy","family":"Pinto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4822-8463","authenticated-orcid":false,"given":"Iyad","family":"Daoudi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romain","family":"Pfeifer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Zamani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8333-1144","authenticated-orcid":false,"given":"Marina","family":"Bousquet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9562-5112","authenticated-orcid":false,"given":"St\u00e9phane","family":"Pyronnet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0304-5186","authenticated-orcid":false,"given":"Christine","family":"Gaspin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Lamant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2610-0144","authenticated-orcid":false,"given":"Fabienne","family":"Meggetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"3018_CR1","doi-asserted-by":"publisher","first-page":"3681","DOI":"10.1182\/blood.V96.12.3681","volume":"96","author":"H Stein","year":"2000","unstructured":"Stein H, Foss HD, Durkop H, Marafioti T, Delsol G, Pulford K, et al. 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