Unexpectedly, when triggering the BCR in CLL cells treated with ibrutinib either in vitro or in vivo, VLA-4 was still capable of being inside-out activated, as clearly determined by both a conformation change consistent with an increased affinity (Chigaev et al., 2009) and an increased capability to form clusters (Spaargaren et al., 2003). Here, BCR is linked to B-cell chronic lymphocytic leukemia.