Importantly, mutation in BIRC3 is associated with activation of non-canonical NF-κB signaling in MCL and CLL, which is quite different from classical NF-κB activation mediated through BCR signaling, and, therefore, this activation of non-canonical NF-κB signaling instructed resistance to ibrutinib [38,39]. The gene discussed is NFKB1; the disease is B-cell chronic lymphocytic leukemia.