ZAP70 expression enhances chemokine‐driven chronic lymphocytic leukemia cell migration and arrest by valency regulation of integrins. Issue 9 (28th March 2018)

• Record Type: Journal Article
• Authors: Laufer, Julia M.; Lyck, Ruth; Legler, Daniel F.
• Is Part Of: FASEB journal. Volume 32:Issue 9(2018)
• Page Start: 4824
• Page End: 4835
• Publication Date: 2018-03-28
• Subjects: CLL -- CCR7 -- CXCR4 -- cell adhesion; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.201701452RR
• Languages: English
• ISSNs: 0892-6638

Abstract

ABSTRACT: 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. FASEB J. 32, 4824–4835 (2018). www.fasebj.org