The Functional Role of Zeta-Chain-Associated Protein 70 in the Pathogenesis of B-Cell Chronic Lymphocytic Leukemia

The aim of this thesis was to investigate the functional role of the prognostic factor ZAP70 in chronic lymphocytic leukemia. The results show that ZAP70 can modify gene expression in leukemic B cells through a mechanism that is distinct from its role as a receptor associated kinase. ZAP70 can translocate to the nucleus in CLL cells, mediated via its kinase domain. The nuclear expression of ZAP70 does affect gene expression likely through an epigenetic mechanism. The altered gene expression in ZAP70-positive CLL cells effects the reduction of GSK3-beta expression, which subsequently stabilises the anti-apoptotic protein Mcl-1. Mcl-1 facilitates resistance to programmed cell death, contributing to the dismal prognosis of ZAP70-positive CLL.