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

Laufer, Julia M; Lyck, Ruth; Legler, Daniel F (2018). ZAP70 expression enhances chemokine-driven chronic lymphocytic leukemia cell migration and arrest by valency regulation of integrins. FASEB journal, 32(9), pp. 4824-4835. Federation of American Societies for Experimental Biology 10.1096/fj.201701452RR

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute
09 Interdisciplinary Units > Microscopy Imaging Center (MIC)

UniBE Contributor:

Lyck, Ruth

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

0892-6638

Publisher:

Federation of American Societies for Experimental Biology

Language:

English

Submitter:

Ruth Lyck

Date Deposited:

28 Feb 2019 11:18

Last Modified:

08 Nov 2019 16:29

Publisher DOI:

10.1096/fj.201701452RR

PubMed ID:

29589978

Uncontrolled Keywords:

CCR7 CLL CXCR4 cell adhesion

BORIS DOI:

10.7892/boris.123828

URI:

https://boris.unibe.ch/id/eprint/123828

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