Here, we investigated the interplay of CXCR4 and VLA-4 during extravasation of tri12 CLL cells compared to those not harboring this aberration (no tri12), finding the chemokine CXCL12 being unable to support BM homing and to efficiently activate VLA-4 in contrast to the successful VLA-4 activation by the LN homing chemokine CCL21. Here, CXCL12 is linked to B-cell chronic lymphocytic leukemia.