Chronic lymphocytic leukemia (CLL) is characterized by genetic heterogeneity and a variety of somatic mutations, the most frequent of which targeting ATM, TP53, NOTCH1, MYD88 and SF3B1 genes. A thorough exploration of these mutations could shed light on the disease etiology, or even lead to the discovery of potential novel drug targets. However, CLL cells extracted from patients do not proliferate ex vivo and thus preclude lengthy experiments, such as CRISPR/Cas9 screening. 76 The aim of this study was to generate stable knockout (ATM, TP53) and knock-in (NOTCH1, SF3B1 and MYD88) CLL cell lines and subsequently use them to investigate unique vulnerabilities specific to these mutations