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Blood, 1 May 2006, Vol. 107, No. 9, pp. 3584-3592.
Prepublished online as a Blood First Edition Paper on December 6, 2005; DOI 10.1182/blood-2005-04-1718.
 Previous Article | Next Article 
Submitted April 27, 2005
Accepted November 6, 2005
ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B cell chronic lymphocytic leukaemia (B-CLL)
Sarah J Richardson*, Christine Matthews, Mark A Catherwood, H Denis Alexander, B Sean Carey, Joanna Farrugia, Anne Gardiner, Sarah Mould, David Oscier, J Adrian Copplestone, and Archibald G Prentice
Department of Haematology, Derriford Hospital, Plymouth, Devon, United Kingdom
Department of Haematology, Belfast City Hospital, Belfast, N. Ireland, United Kingdom
Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom
Department of Haematology, Royal Free and University College Medical School, London, United Kingdom
* Corresponding author; email: Sarah.Richardson{at}phnt.swest.nhs.uk.
Molecular markers like IgVH mutational status, chromosomal abnormalities and CD38 and ZAP-70 expression, have prognostic value in B-cell chronic lymphocytic leukaemia (B-CLL). These may be pathogenetic because of the coincidental expression of ZAP-70 and increased B-cell receptor (BCR) signalling and the signalling 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=0.009; p<0.001) and increased responsiveness to its ligands, CCL19 and CCL21, demonstrated by F-actin polymerisation (p<0.05) and cellular migration (p<0.01). In addition, ZAP-70+ CLL cells exhibit sustained ERK phosphorylation/activation following stimulation with CXCL12 (SDF1- , a survival factor produced by stromal cells), compared to ZAP-70- cells (p=0.004). Following co-culture with nurse-like cells the survival of ZAP-70+ but not ZAP70- CLL cells is significantly enhanced by the addition of CXCL12 (p<0.05), an effect which 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 centres and explain in part the more progressive nature of ZAP-70+ disease.
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