Furthermore, overexpression of CalDAG-GEF1, Rap1B and RAPL in tri12 CLL [34], intracellular molecules playing a crucial role in the VLA-4 inside-out signaling cascade, may lower the threshold for VLA-4 activation by signals other than CXCL12. Here, ARHGEF1 is linked to B-cell chronic lymphocytic leukemia.