Signaling in CLL 2

Zap-70 is the PTK that signals in T cells. Although high Zap-70 expression correlates with poor prognosis in CLL, the precise role of this PTK in CLL is not clear.

In Zap-70-positive CLL cells, it becomes tyrosine phosphorylated and associated with CD79b following BCR engagement and indeed tyrosine phosphorylation of Syk is greater than in Zap-70-negative cells. If you transduce Zap-70 into CLL cells there is enhanced BCR signalling, but this is independent of the PTK activity of Zap-70. Zap-70 may therefore function either as an adaptor protein that augments Syk activation or as a decoy that sequesters a negative regulator of Syk.

Zap-70 may contribute to drug resistance by enhancing migratory responses of CLL cells to the chemokines CCL 19 and 21, thus promoting migration of malignant cells to sites where apoptosis resistance is enhanced by microenvironmental signalling.

The RhoH guanine nucleotide-binding protein contains ITAM motifs and is an adaptor that recruits Zap-70 to T lymphocyte antigen receptors. RhoH is overexpressed in CLL cells relative to normal B cells. Deletion of RhoH retards progression of the CLL-like disease of Eμ-TCL-1 transgenic mice, implying that overexpression of RhoH contributes to CLL pathology by augmenting the contribution of Zap-70 to antigen receptor signalling.

In lay language: Although ZAP-70 positive CLL cells are more malignant, ZAP-70 does not take part in the active signaling process in CLL, the way it does in T-cells. It may act either as an enhancer of Syk activation or as a suprressor of Syk inhibition. It also may act by increasing the response of CLL cells to chemokines, so pushing them into parts of the microenvironment where there are other factors producing resistance to apoptosis.

RhoH is another signaling protein that is important in T cells that is increased in CLL cells. In the TCL-1 animal model for CLL, the disease is retarded if RhoH is deleted, which implies it might have an active role in CLL like that of Zap-70.