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This study aims to investigate the clinical and biological features of CLL with t(14;19)(q32;q13) (tCLL) involving the BCL3 gene. Patients with tCLL were younger and more commonly presented unmutated IGHV gene, subset #8 stereotypy, trisomy of chromosome 12, and complex karyotype than other patients without t(14;19) (oCLL). The presence of t(14;19) was associated with a shorter time to treatment and overall survival compared to oCLL. Gene expression analysis revealed a unique transcriptome profile in tCLL, characterized by the upregulation of BCL3 and the activation of B-cell receptor, PI3K-Akt. Conversely, apoptosis-related pathways were suppressed in tCLL. While the BTK gene was upregulated, the BCL2L11 gene, coding for the pro-apoptotic protein BIM, was downregulated. Notably, patients with tCLL were characterized by a trend (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.058) for a longer time to the next treatment with BTK inhibitors (BTKi) compared to those treated with a venetoclax-based (Ven-based) regimen. We underscore the adverse outcomes of tCLL, its distinct molecular features and gene expression patterns. Therefore, our data suggest that identifying tCLL could help tailor therapeutic approaches.\n                  <\/jats:p>","DOI":"10.1038\/s41375-025-02755-8","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T17:02:08Z","timestamp":1758301328000},"page":"2957-2967","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Clinical and transcriptomic characterization of patients with chronic lymphocytic leukemia harboring t(14;19): an ERIC 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PG received honoraria from AbbVie, AstraZeneca, BeiGene, BMS, Galapagos, Johnson & Johnson, Lilly\/Loxo, MSD, and research funding from AbbVie, AstraZeneca, BeiGene, BMS, Johnson & Johnson, Lilly\/Loxo, MSD. LyS received honoraria from AbbVie, AstraZeneca, BeiGene, Johnson & Johnson, Lilly, and MSD. G.M.R. received honoraria for participation in the speakers\u2019 bureau and advisory board from AbbVie, AstraZeneca, and Janssen. A.C. received honoraria for participation in the speakers\u2019 bureau and advisory board from AbbVie, AstraZeneca, BeiGene, and Janssen Lilly. MD Advisory boards and honoraria: AbbVie, AstraZeneca, Eli Lilly, Johnson and Johnson, Swixx Biopharma. 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