The clinical introduction of the
Bruton's tyrosine kinase (BTK) inhibitor
ibrutinib, which targets
B-cell antigen-receptor (BCR)-controlled
integrin-mediated retention of malignant B cells in their growth-supportive lymphoid organ microenvironment, provided a major breakthrough in
lymphoma and
leukemia treatment. Unfortunately, a significant subset of patients is intrinsically resistant or acquires resistance against
ibrutinib. Here, to discover novel therapeutic targets, we present an unbiased loss-of-adhesion CRISPR-Cas9 knockout screening method to identify
proteins involved in BCR-controlled
integrin-mediated adhesion. Illustrating the validity of our approach, several
kinases with an established role in BCR-controlled adhesion, including BTK and PI3K, both targets for clinically applied inhibitors, are among the top hits of our screen. We anticipate that pharmacological inhibitors of the identified targets, e.g. PAK2 and PTK2B/PYK2, may have great clinical potential as
therapy for
lymphoma and
leukemia patients. Furthermore, this screening platform is highly flexible and can be easily adapted to identify cell adhesion-regulatory
proteins and signaling pathways for other stimuli, adhesion molecules, and cell types.