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(Journal of Leukocyte Biology. 2002;71:495-502.)
© 2002 by Society for Leukocyte Biology

Engagement of 4ß1 integrin by fibronectin induces in vitro resistance of B chronic lymphocytic leukemia cells to fludarabine

M^a Teresa de la Fuente^*, Benito Casanova^*, José V. Moyano^*, Mercedes Garcia-Gila^*, Laura Sanz^*, José Garcia-Marco, Augusto Silva^* and Angeles Garcia-Pardo^*

^* Departamento de Inmunología, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain; and
Servicio de Hematología, Hospital Universitario Clínica Puerta de Hierro, Madrid, Spain

Correspondence: Dr. Angeles Garcia-Pardo, Centro de Investigaciones Biológicas, CSIC, Velázquez 144, 28006 Madrid, Spain. E-mail: agarciapardo{at}cib.csic.es

B-cell chronic lymphocytic leukemia is characterized by the accumulation of malignant B lymphocytes as a result of abnormal survival signals operating in vivo. Previously, we showed that adhesion of B-CLL cells to the fibronectin fragment H89, a ligand for 4ß1 integrin, prevents their spontaneous apoptosis in vitro. We have now studied whether 4ß1/H89 interaction affected the response of B-CLL cells to the therapeutic drug fludarabine. B-CLL cells cultured on H89 during treatment with fludarabine showed significantly higher mean viability (P<0.05) than cells cultured on the control polylysine for all doses of drug tested. Similar results were obtained with the EHEB cell line. Analysis of the expression of Bcl-2-family proteins after 48 h of fludarabine treatment revealed that Bcl-xL levels were significantly higher (P<0.05) for cells cultured on H89 than on polylysine and correlated (r=0.56, P<0.05) with the increased cell viability observed on H89 cultures. These results indicate that Bcl-xL is involved in the survival signals induced by 4ß1 ligation and may contribute to the progressive drug resistance observed in B-CLL.

Key Words: integrin signaling • apoptosis • drug resistance • Bcl-xL

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