ZAP-70+ CLL Cells Have Respond Better to Migratory, Survival Signals

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ZAP-70 expression is associated with enhanced ability to respond to

migratory and survival signals in B cell chronic lymphocytic

leukaemia (B-CLL).

SJ, s C, Catherwood MA, HD, Carey BS,

Farrugia J, Gardiner A, Mould S, Oscier D, Copplestone JA, Prentice

AG.

Department of Haematology, Derriford Hospital, Plymouth, Devon,

United Kingdom.

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-alpha, 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.

PMID: 16332969 [PubMed - as supplied by publisher]