ZAP-70 Promotes the infiltration of malignant B-lymphocytes into the bone marrow by enhancing signaling and migration after CXCR4 stimulation

Eva Calpe, Noelia Purroy, Cecilia Carpio, Pau Abrisqueta, Júlia Carabia, Carles Palacio, Josep Castellví, Marta Crespo, Francesc Bosch

Research output: Contribution to journalArticleResearchpeer-review

10 Citations (Scopus)

Abstract

ZAP-70 in chronic lymphocytic leukemia (CLL) is associated with enhanced response to microenvironmental stimuli. We analyzed the functional consequences of ZAP-70 ectopic expression in malignant B-cells in a xenograft mouse model of disseminated B-cell leukemia. Mice injected with B-cells expressing ZAP-70 showed a prominently higher infiltration of the bone marrow. In vitro analysis of the response of malignant B-cells to CXCL12, the main attracting chemokine regulating trafficking of lymphocytes to the bone marrow, or to bone marrow stromal cells, revealed that ZAP-70 induces an increased response in terms of signaling and migration. These effects are probably mediated by direct participation of ZAP-70 in CXCL12-CXCR4 signaling since CXCR4 stimulation led to activation of ZAP-70 and downstream signaling pathways, such as MAPK and Akt, whereas ZAP-70 did not alter the expression of the CXCR4 receptor. In addition, subclones of primary CLL cells with high expression of ZAP-70 also showed increased migrative capacity toward CXCL12. Neutralization of CXCR4 with a monoclonal antibody resulted in impaired in vitro responses to CXCL12 and bone marrow stromal cells. We conclude that ZAP-70 enhances the migration of malignant B-cells into the supportive microenvironment found in the bone marrow mainly by enhancing signaling and migration after CXCR4 stimulation. © 2013 Calpe et al.
Original languageEnglish
Article numbere81221
JournalPLoS ONE
Volume8
Issue number12
DOIs
Publication statusPublished - 3 Dec 2013

Fingerprint Dive into the research topics of 'ZAP-70 Promotes the infiltration of malignant B-lymphocytes into the bone marrow by enhancing signaling and migration after CXCR4 stimulation'. Together they form a unique fingerprint.

Cite this