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-García, Carles (Hospital Universitari Vall d'Hebron)
Castellvi, Josep (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Crespo Maull, Marta (Vall d'Hebron Institut d'Oncologia)
Bosch Albareda, Francesc 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 PI11/00792 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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