Engagement of alpha4beta1 integrin by fibronectin induces in vitro resistance of B chronic lymphocytic leukemia cells to fludarabine.
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 alpha4beta1 integrin, prevents their spontaneous apoptosis in vitro. We have now studied whether alpha4beta1/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 alpha4beta1 ligation and may contribute to the progressive drug resistance observed in B-CLL.
de la Fuente
Maria Teresa
MT
Departamento de Inmunología, Centro de Investigaciones Biológicas, CSIC, Velázquez 144, 28006 Madrid, Spain.
Casanova
Benito
B
Moyano
José V
JV
Garcia-Gila
Mercedes
M
Sanz
Laura
L
Garcia-Marco
José
J
Silva
Augusto
A
Garcia-Pardo
Angeles
A
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D005353:Fibronectins; D039041:Integrin alpha4beta1; D016023:Integrins; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D016201:Receptors, Lymphocyte Homing; D051020:bcl-X Protein; D014740:Vidarabine; C024352:fludarabine