CD20 antigen has been used as a target of monoclonal antibodies (mAb) such as rituximab (RTX) in the therapy of B-cell malignancies for more than two decades. However, CLL B cells tend to express lower levels of CD20 on their surface or downregulate it following the mAb treatment, resulting in mAb resistance and subsequently therapy failure. Therefore, it is crucial to investigate the regulation of CD20 in order to restore sensitivity to anti-CD20 mAb and enhance its efficacy. The aim of this project was to perform genome-wide CRISPR/Cas9 knockout screening to identify genes whose disruption upregulates CD20 surface expression in the resistant cells with low CD20 levels.