Examples of subclonal CLL drivers include mutations within ATM, SF3B1, TP53 and BIRC3. In addition to genomic analyses, transcriptome profiling studies (e.g. bulk RNA-seq) demonstrate global transcriptional changes that often accompany genetic clonal evolution (46–48), while epigenomic studies such as genome-scale DNA methylation analyses on bulk CLL cell populations reveal remarkable intratumoral epigenetic heterogeneity that fuels clonal evolution (49). This evidence concerns the gene SF3B1 and B-cell chronic lymphocytic leukemia.