The genomic and transcriptomic landscape of chronic lymphocytic leukaemia: Insights from an integrated analysis of 275 patients

Summary Chronic lymphocytic leukaemia (CLL) exhibits marked clinical and molecular heterogeneity. While previous studies have primarily focused on gene mutations, the broader landscape of genomic alterations and their clinical significance remains incompletely characterized. We analysed 275 patients with CLL using a comprehensive next‐generation sequencing assay that assessed mutations, gene rearrangements and ribonucleic acid (RNA) expression, integrated with cytogenetic/fluorescence in situ hybridization (FISH) data, immunoglobulin heavy chain variable region (IGHV) status and clinical outcomes. The most frequently mutated genes were TP53 , NOTCH1 , ATM , BIRC3 and SF3B1 . RNA analysis revealed recurrent upregulation of B‐cell–associated genes, including PAX5 , CREB3L2 , FOXP1 , SH3BP5 , CCDC50 and PTPN1 . Novel gene rearrangements were identified, including CBFB::DNTTIP1 , IGH::PDCD1LG2 and PPP2R5C::TERT . KRAS mutation was independently associated with inferior overall survival (OS), whereas XPO1 mutation and age ≥ 65 years were adverse factors for time to first treatment (TTFT). Patients without detectable mutations exhibited more favourable disease features, including mutated IGHV, fewer cytogenetic abnormalities, higher rates of increased 13q deletion, lower rates of 17p deletion and longer TTFT. Although elevated RNA expression was not directly associated with OS or TTFT, distinct mutation‐associated expression patterns were observed. These findings demonstrate that integrated genomic and transcriptomic profiling can identify clinically relevant molecular subsets in CLL, potentially refining risk stratification and informing future studies.