Abstract
This thesis describes a number of studies that investigated several aspects of apoptosis in lymphoid malignancies. Resistance to apoptosis is an important asset of cancer cells, which allows them to evade cell death signals instigated by the changes they undergo during transformation, such as genetic alterations leading to aberrant cell cycle control, enhanced mitogenic potential and independence of growth signals. Reduced sensitivity to apoptosis also contributes to the resistance to chemo- and radiotherapy that often limits the clinical efficacy of cancer therapy. Apoptosis is an important mechanism for several aspects of normal B- and T-cells physiology and functioning of the immune system. Aberrations in apoptosis pathways may therefore play a prominent role in leukaemia and lymphoma, as suggested by the t(14;18) translocation in follicular lymphoma targeting anti-apoptotic Bcl-2 and the t(11:18) translocation in MALT lymphoma targeting c-IAP2. To get a better understanding of the resistance to apoptosis in cancer, we need to unravel the basic mechanisms that control apoptosis. Mitochondria play a critical role in the apoptotic pathway that is initiated in response to intracellular signals. Bcl-2 family members are the principal regulators of the mitochondrial pathway of apoptosis that control the release of apoptogenic factors from the mitochondria into the cytosol. However, the exact mechanisms by which Bcl-2 family proteins regulate this release are not fully understood. Bcl-2 family members have been implicated to interfere with several mitochondrial functions that may play a role in apoptosis. In the first two chapters, we focussed on the interplay between Bcl-2 and mitochondria. In addition to functional regulation through biochemical pathways, apoptosis is controlled by transcriptional regulation of apoptotic genes. Altered expression of apoptotic genes is shown to be an important aspect that contributes to apoptosis deregulation in cancer. In the second part of this thesis we focussed on the expression of apoptosis-regulating genes in haematological malignancies.
