UNLABELLED: In Chronic Lymphocytic Leukemia (CLL), t(14;19)(q32;q13), leading to the overexpression of BCL3, is found in ∼1% of cases and is associated with an aggressive disease. In this study, leveraging a large CLL patient cohort collected thanks to an international collaboration, we investigate for the first time the circular transcriptome (circRNAome) associated with the rare t(14;19), in comparison with CLL without t(14;19) and B cells of age-matched healthy donors. We described the circRNAs commonly dysregulated in CLL, including circCSNK1G3 and circEXOC6B(3–5), which were depleted, and circZNF609 and circLPAR3, which were overexpressed in malignant cells. Of importance, we disclosed the circRNA signature of CLL with t(14;19), formed by circRNAs with expression significantly altered specifically in link with this lesion, ectopically expressed like circCDK14(3–4), circCORO1C, circCLEC2D, and circEMB, or downregulated like circCEP70(3–6). Several of these molecules were previously shown to be dysregulated or play a role in cancer, whereas most of the signature circRNAs deserve further investigation. CLL patients with high circCORO1C and circCLEC2D expression had significantly worse clinical outcomes, with shorter time to first treatment and overall survival. This study disclosed new molecular features of the aggressive CLL subtype with t(14;19). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13045-025-01725-y.

1st Department of Propaedeutic University of Athens Athens Greece

Computational Genomics Group Department of Surgery Oncology and Gastroenterology University of Padua Padova Italy

Department 1 of Internal Medicine University of Cologne Cologne Germany

Department of Biology University of Padua Padova Italy

Department of Hematology Cancer Center Amsterdam and Lymphoma and Myeloma Center Amsterdam Amsterdam The Netherlands

Department of Hematology Vall d'Hebron Institute of Oncology Hospital Universitari Vall d'Hebron Barcelona Spain

Department of Immunology Genetics and Pathology and Clinical Genomics Uppsala Science for Life Laboratory Uppsala University Uppsala Sweden

Department of Internal Medicine Hematology and Oncology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Molecular Medicine University of Padua Padova Italy

Department of Translational and Precision Medicine Hematology Unit 'Sapienza' University Rome Italy

Division of Experimental Oncology IRCCS Ospedale San Raffaele Milano Italy

Federal State Budgetary Educational Institution of Higher Education Academician 1 P Pavlov 1st St Petersburg State Medical University of the Ministry of Healthcare of Russian Federation St Petersburg Russia

Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece

Hematology Section Department of Medical Sciences Arcispedale S Anna Azienda Ospedaliera Universitaria University of Ferrara Ferrara Italy

Hematology Unit Department of Medicine University of Padua via N Giustiniani 2 35128 Padova Italy

Immunology and Molecular Oncology Unit Veneto Institute of Oncology IOV IRCSS Padova Italy

Institute of Applied Biosciences Center for Research and Technology Hellas Thessaloniki Greece

Laboratoire d'hématologie Hôpital Avicenne Assistance Publique Hôpitaux de Paris Paris France

Medical School Università Vita Salute San Raffaele Milano Italy

MLL Munich Leukemia Laboratory Munich Germany

Molecular Cytogenetics Laboratory Pathology Department Translational Research on Hematological Neoplasms Group Cancer Research Program Hospital del Mar Hospital del Mar Research Institute Barcelona Spain

Molecular Pathology University Hospitals Dorset Royal Bournemouth Hospital Bournemouth UK

Service d'Hématologie Biologique Hôpital Pitié Salpêtrière Paris France

Servicio de Genética Hospital Universitario de Navarra Pamplona Spain

Servicio de Hematología y Oncología Médica Hospital Clinico Universitario de Valencia Valencia Spain

State Key Laboratory of Experimental Hematology Haihe Laboratory of Cell Ecosystem Institute of Hematology and Blood Diseases Hospital National Clinical Research Center for Blood Diseases Chinese Academy of Medical Sciences and Peking Union Medical College Tianjin Institutes of Health Science Tianjin China

The Ohio State University Comprehensive Cancer Center Columbus OH USA

Ulm University Ulm Germany

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