title: ZAP-70 enhances migration of malignant B lymphocytes toward CCL21 by inducing CCR7 expression via IgM-ERK1/2 activation.
abstract: ZAP-70 in chronic lymphocytic leukemia (CLL) has been associated with enhanced B-cell receptor (BCR) signaling, survival, and migration. We investigated whether ZAP-70 can directly govern migration and the underlying mechanisms. In the ZAP-70 stably transfected Ramos cell line, IgM stimulation, but no IgD, enhanced phosphorylation of ERK1/2, Akt and Syk, and delayed IgM and CD79b internalization. In contrast, in the Raji cell line, where ZAP-70 was constitutively phosphorylated, ERK1/2, but not Akt, was phosphorylated, suggesting that MAPK pathway mediates ZAP-70 effects. BCR stimulation modulated the expression of CCR7, CXCR4, CXCR5, CD44, CD49d, and CD62L, which were up-regulated in ZAP-70-positive CLL primary subclones. The most dramatic change after BCR engagement in ZAP-70-transfected cells was CCR7 up-regulation, this being impaired by ERK1/2 inhibition and translating into both increased signaling and migration toward CCL21. Primary CLL subclones with high ZAP-70 expression showed increased migration toward CCL21. In conclusion, ZAP-70 ectopic expression led to enhanced BCR signaling after IgM stimulation and increased the expression of CCR7 predominantly via ERK1/2, increasing the response and migration toward CCL21. In primary CLL samples, cellular subsets with high ZAP-70 expression had increased expression of adhesion molecules and chemokine receptors in addition to an enhanced ability to migrate toward CCL21.
authors.affiliation: Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Calpe
authors.forename: Carles
authors.initials: C
authors.lastname: Codony
authors.forename: Maria Joao
authors.initials: MJ
authors.lastname: Baptista
authors.forename: Pau
authors.initials: P
authors.lastname: Abrisqueta
authors.forename: Cecilia
authors.initials: C
authors.lastname: Carpio
authors.forename: Noelia
authors.initials: N
authors.lastname: Purroy
authors.forename: Francesc
authors.initials: F
authors.lastname: Bosch
authors.forename: Marta
authors.initials: M
authors.lastname: Crespo
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002051:Burkitt Lymphoma / Q000276:immunology*; D045744:Cell Line, Tumor; D054421:Chemokine CCL21 / Q000276:immunology*; D002633:Chemotaxis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology*; D020935:MAP Kinase Signaling System; D054400:Receptors, CCR7 / Q000235:genetics / Q000276:immunology*; D014407:Tumor Cells, Cultured; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000276:immunology*
chemical_list: D054421:Chemokine CCL21; D007075:Immunoglobulin M; D054400:Receptors, CCR7; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human