ZAP-70 Promotes the Infiltration of Malignant B-Lymphocytes into the Bone Marrow by Enhancing Signaling and Migration after CXCR4 Stimulation
Calpe, Eva (Hospital Universitari Vall d'Hebron)
Purroy i Zuriguel, Noèlia (Hospital Universitari Vall d'Hebron)
Carpio Segura, Cecilia del Carmen (Hospital Universitari Vall d'Hebron)
Abrisqueta, Pau (Hospital Universitari Vall d'Hebron)
Carabia, Júlia (Hospital Universitari Vall d'Hebron)
Palacio, Carles (Hospital Universitari Vall d'Hebron)
Castellvi, Josep (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Crespo, Marta (Vall d'Hebron Institut d'Oncologia)
Bosch José, Francesc Xavier 1947- (Hospital Universitari Vall d'Hebron)
Universitat Autònoma de Barcelona

Data:	2013
Resum:	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.
Ajuts:	Ministerio de Ciencia e Innovación PI 11/00792 Ministerio de Economía y Competitividad RYC-2012-12018
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	PloS one, Vol. 8 (december 2013) , ISSN 1932-6203

DOI: 10.1371/journal.pone.0081221
PMID: 24312539

10 p, 2.2 MB

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