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

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.

ZAP-70 Shapes the Immune Microenvironment in B Cell Malignancies

“…This finding is consistent with previous studies showing ZAP-70 expression in CLL cells correlates with CCR7 expression, induced by IgMmediated ERK activation, thus enhancing the migratory ability to CCL19 and CCL21 (34,35). A recent study has further evidenced this in CLL patients, and observed that ZAP-70 positive CLL cells migrated more to CCL19, CCL21, and CXCL12 by controlling the chemokine-driven clustering of the integrins VLA-4 and LFA-1 (36). Moreover, ZAP-70 expression also correlates with CCR7/CXCR4 expression in B cell precursor ALL disease and here promotes migration toward CCL19/CXCL12 in the central nervous system (37).…”

CCR7 Is Recruited to the Immunological Synapse, Acts as Co-stimulatory Molecule and Drives LFA-1 Clustering for Efficient T Cell Adhesion Through ZAP70

“…Moreover, CXCR4-induced ZAP70 activation results in phosphorylation of Vav1, a guanine nucleotide exchange factor for Rac/Rho GTPases, and its dissociation from talin enabling talin-integrin association and hence, inside-out signaling and activation of the integrin very late antigen-4 (VLA-4) in T cells (19–21). Remarkably, we recently identified ZAP70, which is aberrantly expressed in chronic lymphatic leukemia (CLL), to enhance chemokine-driven CLL arrest by promoting integrin clustering (22).…”

Integrative Bioinformatics Approaches to Screen Potential Prognostic Immune-Related Genes and Drugs in the Cervical Cancer Microenvironment

“…CCR7 has been reported to influence the lymph node metastasis of cervical cancer, prostate cancer cell migration, and mammary cancer cell stemness (Boyle et al, 2017;Dai et al, 2017;Maolake et al, 2018). Tyrosine kinase ZAP70 has been identified to play a key role in T cell activation and the immune response (Fu et al, 2016;Alsadeq et al, 2017;Laufer et al, 2018).…”