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B cell chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, responsible for more than 5000 deaths annually in the United States. The clinical course of CLL varies; some patients have an indolent course with no need for therapy, while others succumb to the disease within a few years. It has recently been shown that cases can be divided into two subgroups based on the presence or absence of rearranged immunoglobulin heavy chain variable region (IgVH) genes of the leukemic cells. Patients with rearranged IgVH genes (50-70% of patients) fare much better than those with germline IgVH genes, with median survivals being more than 24 years and 6 to 8 years respectively.

Since knowledge of IgVH rerrangement is of considerable value in assessing prognosis in CLL, and since direct analysis of IgVH genes is technically demanding and expensive, a surrogate marker for IgVH mutational status has been actively sought. Expression of CD38 by CLL leukemic cells was initially proposed as a surrogate marker for IgVH rearrangement, however subsequent studies failed to confirm CD38 as an independent and consistent prognostic factor. ZAP-70 is an enzyme involved in the signal transduction network that links T cell receptor MHC-antigen complex binding to downstream signaling pathways. Gene expression profiling has demonstrated that ZAP-70 is also expressed in IgVH germline CLL B-cells.

Early studies demonstrated an association of intracellular ZAP-70 expression with germline IgVH and with disease progression. More than 50 research articles have subsequently been published on this topic. Today, there is less enthusiasm for use of a flow cytometry based ZAP-70 assay for CLL patients, largely because of the failure to develop a reliable, standardized method. 

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