Insights into genetic aberrations and signalling pathway interactions in chronic lymphocytic leukemia: from pathogenesis to treatment strategies.

Abstract

Chronic lymphocytic leukemia (CLL) is prevalent in adults and is characterized by the accumulation of mature B cells in the blood, bone marrow, lymph nodes, and spleens. Recent progress in therapy and the introduction of targeted treatments [inhibitors of Bruton's tyrosine kinase (BTKi) or inhibitor of anti-apoptotic B-cell lymphoma-2 (Bcl-2i) protein (venetoclax)] in place of chemoimmunotherapy have significantly improved the outcomes of patients with CLL. These advancements have shifted the importance of traditional predictive markers, leading to a greater focus on resistance genes and reducing the significance of mutations, such as TP53 and del(17p). Despite the significant progress in CLL treatment, some patients still experience disease relapse. This is due to the substantial heterogeneity of CLL as well as the interconnected genetic resistance mechanisms and pathway adaptive resistance mechanisms to targeted therapies in CLL. Although the knowledge of the pathomechanism of CLL has expanded significantly in recent years, the precise origins of CLL and the interplay between various genetic factors remain incompletely understood, necessitating further research. This review enhances the molecular understanding of CLL by describing how BCR signalling, NF-κB PI3K/AKT, and ROR1 pathways sustain CLL cell survival, proliferation, and resistance to apoptosis. It also presents genetic and pathway-adaptive resistance mechanisms in CLL. Identifying B-cell receptor (BCR) signalling as a pivotal driver of CLL progression, the findings advocate personalized treatment strategies based on molecular profiling, emphasizing the need for further research to unravel the complex interplay between BCR signalling and its associated pathways to improve patient outcomes.