Complexity of apoptotic pathways in leukemia treated with chemotherapy or cellular immunotherapy

Abstract

One of the major problems in the treatment of patients with acute leukemia is failure of therapy due to acquired resistance, which may partially be caused by defects in the apoptotic machinery of these leukemic cells. Apoptosis is induced and regulated by a complex network of proteins connected via various signal transduction cascades, eventually leading to death of the target cell. The results described in this thesis demonstrate that apoptosis induction in leukemic cells after treatment with chemotherapy or (cellular) immunotherapy is very complex and frequently dependent on the target cell studied, and on the interaction between target and effector cell. G0 cells derived from patients with B-CLL compared to G0 cells from patients with acute leukemia responded differently to Ara-C treatment, which may be partially explained by the different mechanisms of action exerted by Ara-C. The role of the death receptor pathway in both chemotherapy-induced and CTL-induced apoptosis of leukemic cells was also unraveled in more detail. It will be worthwhile to focus future strategies in the treatment of leukemia on modulation or activation of proteins that are common in multiple apoptotic pathways, like caspase-8, since this approach will sensitize the leukemic cells simultaneously to chemotherapy and cellular immunotherapy.