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Here, we investigated the expression and inducibility of IL-12 family receptor subunits (IL-23R, IL-12R\u03b21, IL-12R\u03b22) and the related receptor complexes in recirculating CLL cells, with a focus on CXCR4\/CD5-defined fractions: the proliferative fraction (PF; CXCR4dim\/CD5bright; most recently divided, tissue-emigrated cells) and the resting fraction (RF; CXCR4bright\/CD5dim; older, quiescent cells). At baseline, IL-12R\u03b21 was enriched in the PF and was associated with a higher proportion of cells expressing IL-23R and IL-12R receptor complexes. Concomitantly, RT-qPCR disclosed higher IL-12R\u03b21 mRNA levels. Following antigen-independent activation with CpG or CpG + IL-15, there was a marked increase in IL-23R and IL-12R\u03b21 but not in IL-12R\u03b22 surface expression, resulting in preferential upregulation of the IL-23R complex over the IL-12R complex. Fraction-specific analyses showed stronger induction of IL-23R and IL-23R complex expression in PF compared with RF. These findings identify an intraclonal bias toward IL-23 responsiveness in the CLL cells with a phenotype of recently divided, tissue-emigrated cells and suggest the IL-23\/IL-23R axis as a potential therapeutic target.<\/jats:p>","DOI":"10.3390\/ijms27031202","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T08:14:23Z","timestamp":1769415263000},"page":"1202","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intraclonal Enrichment of IL-23 Receptor Complex Expression in the Proliferative Fraction of Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0386-6611","authenticated-orcid":false,"given":"Martina","family":"Cardillo","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5097-6640","authenticated-orcid":false,"given":"Fabiana","family":"Ferrero","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy"},{"name":"Molecular Pathology Unit, IRCCS Azienda Ospedaliera Metroplitana, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4591-3260","authenticated-orcid":false,"given":"Nadia","family":"Bertola","sequence":"additional","affiliation":[{"name":"Molecular Pathology Unit, IRCCS Azienda Ospedaliera Metroplitana, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1479-8121","authenticated-orcid":false,"given":"Ennio","family":"Nano","sequence":"additional","affiliation":[{"name":"Molecular Pathology Unit, IRCCS Azienda Ospedaliera Metroplitana, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosanna","family":"Massara","sequence":"additional","affiliation":[{"name":"Molecular Pathology Unit, IRCCS Azienda Ospedaliera Metroplitana, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Cristina","family":"Capra","sequence":"additional","affiliation":[{"name":"Molecular Pathology Unit, IRCCS Azienda Ospedaliera Metroplitana, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniele","family":"Reverberi","sequence":"additional","affiliation":[{"name":"Molecular Pathology Unit, IRCCS Azienda Ospedaliera Metroplitana, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5512-8106","authenticated-orcid":false,"given":"Monica","family":"Colombo","sequence":"additional","affiliation":[{"name":"Molecular Pathology Unit, IRCCS Azienda Ospedaliera Metroplitana, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7302-7429","authenticated-orcid":false,"given":"Vanessa","family":"Cossu","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy"},{"name":"Molecular Pathology Unit, IRCCS Azienda Ospedaliera Metroplitana, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2301-8698","authenticated-orcid":false,"given":"Fabio","family":"Ghiotto","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adalberto","family":"Ibatici","sequence":"additional","affiliation":[{"name":"Hematology and Cellular Therapy Unit, IRCCS Azienda Ospedaliera Metroplitana, 16132 Genova, 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