Functional and prognostic role of ZAP-70 in chronic lymphocytic leukaemia.

It has become clear that the heterogeneity of chronic lymphocytic leukaemia (CLL) is not a continuous spectrum, but is bipolar. Originally distinguished by the mutational status of the immunoglobulin variable region genes, the two poles are perhaps better identified by the expression of ZAP-70, a signalling molecule normally utilised by T cells rather than B cells, but anomalously expressed in the more aggressive subtype of CLL. Assaying ZAP-70 expression has become progressively simplified so that a directly stained flow cytometric test is currently being evaluated, and a version of this should shortly be available to routine laboratories. In addition, the understanding of the nature of CLL has been advanced rapidly and this should lead to new, better targeted therapies, which in contrast to the current armoury, will work better for the more malignant variants of CLL than for the more benign. In particular, ZAP-70 is especially attractive because its aberrant expression in tumour cells from the more aggressive forms of CLL requires the chaperoning action of activated heat-shock protein 90, which may be specifically inhibited.