Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia

Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole exome sequencing data of 8 chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. We identified recurrent mutations in BTG1 and homozygous deletions affecting CDKN2A/B that developed during treatment, as well as a mutation in BRAF and a high-level focal amplification of CD274 (PD-L1) that might pinpoint molecular aberrations offering structures for further therapeutic interventions.