ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B-cell chronic lymphocytic leukemia (B-CLL)

Molecular markers like IgVH mutational status, chromosomal abnormalities, and CD38 and ZAP-70 expression have prognostic value in B-cell chronic lymphocytic leukemia (B-CLL). These may be pathogenetic because of the coincidental expression of ZAP-70 and increased B-cell receptor (BCR) signaling and...

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Bibliographic Details
Published in:Blood 2006-05, Vol.107 (9), p.3584-3592
Main Authors: Richardson, Sarah J., Matthews, Christine, Catherwood, Mark A., Alexander, H. Denis, Carey, B. Sean, Farrugia, Joanna, Gardiner, Anne, Mould, Sarah, Oscier, David, Copplestone, J. Adrian, Prentice, Archibald G.
Format: Article
Language:English
Subjects:
Biological and medical sciences
Case-Control Studies
Cell Movement
Cell Survival
Chemokine CCL19
Chemokine CCL21
Chemokine CXCL12
Chemokines, CC - pharmacology
Chemokines, CXC - pharmacology
Genes, Immunoglobulin
Hematologic and hematopoietic diseases
Humans
In Vitro Techniques
Leukemia, Lymphocytic, Chronic, B-Cell - enzymology
Leukemia, Lymphocytic, Chronic, B-Cell - genetics
Leukemia, Lymphocytic, Chronic, B-Cell - immunology
Leukemia, Lymphocytic, Chronic, B-Cell - pathology
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
MAP Kinase Signaling System - drug effects
Medical sciences
Models, Biological
Mutation
Receptors, CCR7
Receptors, Chemokine - metabolism
Receptors, CXCR4 - metabolism
Signal Transduction
ZAP-70 Protein-Tyrosine Kinase - metabolism
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Summary:Molecular markers like IgVH mutational status, chromosomal abnormalities, and CD38 and ZAP-70 expression have prognostic value in B-cell chronic lymphocytic leukemia (B-CLL). These may be pathogenetic because of the coincidental expression of ZAP-70 and increased B-cell receptor (BCR) signaling and the signaling function of CD38 in CLL. This study shows that ZAP-70+ CLL B cells respond in vitro more readily than ZAP-70– CLL and normal B cells to chemokine migratory signals through enhanced surface CCR7 expression (P = .009; P < .001) and increased responsiveness to its ligands CCL19 and CCL21, demonstrated by F-actin polymerization (P < .05) and cellular migration (P < .01). In addition, ZAP-70+ CLL cells exhibit sustained ERK phosphorylation/activation following stimulation with CXCL12 (SDF1-α, a survival factor produced by stromal cells) compared with ZAP-70– cells (P = .004). Following coculture with nurse-like cells, the survival of ZAP-70+ but not ZAP-70– CLL cells is significantly enhanced by the addition of CXCL12 (P < .05), an effect that is partially blocked by the MEK inhibitor PD98059. These advantageous migratory and survival responses may promote easier access to and greater proliferation in pseudo-germinal centers and explain in part the more progressive nature of ZAP-70+ disease.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2005-04-1718