Our parallel CRISPR-Cas9 screening in DLBCL cells with kinase-active versus kinase-inactive BTK revealed an increased genetic dependency of BTK kinase-inactive cells on TLR9, UNC93B1, CNPY3, and HCK. Thus, inactivation of BTK kinase activity resulted in a loss of cellular fitness only when these genes were inactivated. Here, UNC93B1 is linked to diffuse large B-cell lymphoma.