BIRC3 was found to be recurrently disrupted by mutations, deletions, or a combination of mutations and deletions in CLL patients.15BIRC3 inactivating mutations and a fraction of BIRC3 deletions cause a truncation of the C-terminal RING domain of the BIRC3 protein, essential for ubiquitination, and the following proteasome degradation, of MAP3K14, and drives constitutive non-canonical NF-κB activation (Figure 1).15 Here, NFKB1 is linked to B-cell chronic lymphocytic leukemia.