Cd38

Broad hemopoietic expression. High-level expression on plasma cells. High expression in poor prognosis CLL.

CD38 is a cyclic ADP-ribose hydrolase.

ZAP70 Normal T cells Intracellular kinase that transduces signals from the T-cell

Various B-cell and T-cell antigen receptor involved in BCR signaling in CLL.16

malignancies May also be involved in CXCR4/SDF1 signaling

Low-level expression in CLL Predominantly nuclear expression in CLL17 with unmutated IGHV gene segments.

ZAP70 Normal T cells Intracellular kinase that transduces signals from the T-cell

Various B-cell and T-cell antigen receptor involved in BCR signaling in CLL.16

malignancies May also be involved in CXCR4/SDF1 signaling

Low-level expression in CLL Predominantly nuclear expression in CLL17 with unmutated IGHV gene segments.

and CD71, whereas, conversely, all exhibit down-regulation of CD22, Fc^RIIb, CD79b, and IgD, molecules known to be down-regulated by cell triggering and activation. This composite phenotype is typical of memory B cells and is consistent with the gene expression profile of CLL.

The immunophenotype of CLL proliferation centers, however, differs significantly from that of cells in the peripheral blood.216 Such cells express Ki67, high-levels of CD20 and CD23, and unlike cells in the peripheral blood survivin. Whether cells in the proliferation centers preferentially express activation-induced cytidine deaminase (AID), an enzyme necessary for somatic hypermutation (SHM), class-switching of the IGH genes, and expressed in only a subclone in CLL, is not yet known.19 These and other data discussed below indicate that the proliferating cells in CLL may have a different phenotype and behavior from the bulk of cells in the peripheral blood.

The best molecule for prognostic evaluation is the intracellular tyrosine kinase, ZAP70.20 This molecule was found to be expressed in CLL from gene expression profiling (GEP) experiments. This was an unanticipated finding, as until then ZAP70 had been described as a T-cell specific molecule involved in signal trans-duction from the T-cell receptor for antigen. ZAP70 expression has since been described in a variety of B-cell malignancies, where its expression is unexpectedly within the nucleus rather than the cytoplasm (Table 22.1). Its functions in B-cell malignancies are unknown, although it has been suggested that, as in T-cells, it may be involved in signal transduction from the B-cell receptor (BCR) for antigen(reviewed in Ref. 16). The major clinical interest in ZAP70 in CLL is that expression correlates strongly with absence of mutations within the IGHV region gene segments (qv), and may substitute for IGHV mutational analysis. ZAP70 expression may be detected by flow cytometry, although problems with using this method include expression in residual T-cells and the low-level expression of the molecule in CLL.21 High ZAP70 expression correlates with a more aggressive clinical course.

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