Genetic evolution in chronic lymphocytic leukaemia

•Next-generation sequencing has uncovered the molecular basis of CLL.•Some newly discovered drivers could be targeted pharmacologically.•Clonal evolution emerges as a common cause for disease refractoriness.

Next-generation sequencing provides a comprehensive understanding of the genomic, epigenomic and transcriptomic underpinnings of chronic lymphocytic leukaemia. Recent studies have uncovered new drivers, including mutations in non-coding regions, and signalling pathways whose role in cancer was previously unknown or poorly understood. Moreover, massive scale epigenomics and transcriptomics have supplied the foundations for the cellular origin of the disease. Some drivers could be targeted pharmacologically, and the ability to detect mutations present in minority subclones might even allow treatment before clonal selection occurs, thus preventing disease refractoriness. As our understanding broadens and ongoing technological innovation propels new achievements, we will certainly learn how to apply it in our daily practice.