ZAP70 expression enhances chemokine-driven chronic lymphocytic leukemia cell migration and arrest by valency regulation of integrins.

The ζ-associated protein of 70 kDa (ZAP70) is expressed in the aggressive form of B-cell chronic lymphocytic leukemia (CLL). Moreover, the integrin very late antigen (VLA)-1 is highly expressed on subtypes of CLL that are associated with high proliferation rates in the lymph node context. We herein identify a critical role for ZAP70 in chemokine-mediated, inside-out signaling to integrins in trisomy 12 carrying Ohio State University-CLL cell lines derived from a patient with previously treated CLL. We found that ZAP70-positive CLL cells migrated significantly better toward ligands of the lymph node homing chemokine receptors CCR7 and CXCR4 compared with ZAP70-negative cells. In addition, ZAP70-expressing CLL cells adhered more efficiently to integrin ligands under static conditions. We discovered that ZAP70 expression controls chemokine-driven clustering of the integrins VLA-4 and lymphocyte function-associated antigen-1. More precisely, chemokine stimulation resulted in a ZAP70-dependent integrin valency regulation on CLL cells, whereas high-affinity regulation of integrins was independent of ZAP70. Consequently, ZAP70-expressing CLL cells show increased chemokine-driven arrest on immobilized integrin ligands and on chemokine-presenting endothelial cells under physiologic flow conditions. Hence, we describe a novel mechanism showing how ZAP70 controls chemokine-driven valency regulation of integrins and arrest of CLL cells on endothelial cells, a process that might contribute to CLL disease progression.-Laufer, J. M., Lyck, R., Legler, D. F. ZAP70 expression enhances chemokine-driven chronic lymphocytic leukemia cell migration and arrest by valency regulation of integrins.