title: The role of the Bcl-2 family of proteins in the pathogenesis of B-cell chronic lymphocytic leukaemia
Creators: name: Kennedy, Andrew
Publisher: name: University of Glasgow
Year: 2000
Subjects: subject: Oncology.

description: B-cell chronic lymphocytic leukaemia (B-CLL) is an acquired neoplastic disease characterised by a clonal accumulation of long-lived, functionally immature and CD5+ B-lymphocytes, which particularly accumulate in the lymphatic system, peripheral blood, bone marrow, spleen and liver. Symptoms include lymphocytosis, immune system dysfunction and autoimmune disease, but transformation to more aggressive forms of neoplastic disease occur and development of a second malignancy is not uncommon. The disease is one of later years being unusual before 50 years of age, the rates of incidence vary on a racial basis, and it has a highly variable prognosis. Some patients die within months of diagnosis despite intensive treatment, whilst others survive for 30-plus years without any form of medical intervention and die of unrelated causes. The principal causes of death in patients whose deaths are directly related to the disease are opportunistic infection due to the impairment of immune system function and bleeding disorders. No treatment has been shown to cure the disease or consistently extend life expectancy. It has been recognised for more than 30 years that the accumulation of malignant cells in B-CLL is at least as important in the pathogenesis of the disease as their neoplastic proliferation. With the discoveries that Bcl-2 extended the life of follicular lymphoma cells by conferring resistance to apoptosis and was commonly expressed in B-CLL cells, it was extrapolated that Bcl-2 might play a similar role in the development of the disease by extending the life span of B-CLL cells. Bcl-2 has frequently been shown to be over expressed in B-CLL cells and genetic translocations and/or malfunction of Bcl-2 family regulating molecular entities may play a part in this. However, since its discovery, Bcl-2 has been shown to be part of a large family of genes which is highly and evolutionarily conserved. Members of the bcl-2 family are defined by sequence homology in four Bcl-2 homology (BH) regions and a hydrophobic membrane-spanning domain, with the possession of specific BH domains determining whether individual proteins have pro- or anti-apoptotic activity. Family members such as Bcl-2 and Bcl-XL extend the life span of cells, whilst others such as Bax and Bak shorten it. Oltvai, Milliman and Korsmeyer have proposed a general model of apoptosis, in which the cell's apoptotic fate is determined by the cellular balance between pro- and anti-apoptotic bcl-2 family members. The effect of unregulated expression of Bcl-2 family members in B-CLL cells conforms to this paradigm and resistance to apoptosis appears to be conferred through a cellular imbalance of power between pro- and anti-apoptotic bcl-2 family members, particularly Bcl-2 and Bax, which is tilted in favour of cell survival. However, the apoptotic fate of B-CLL cells, and hence the neoplasm, may be influenced by other family members, with Mcl-1, Bcl-XL, Bak, with the non-family but Bcl-2-associated protein, Bag-1, also found expressed in B-CLL cells. Similarities between the structure of the more conserved family members and other pore-forming proteins, along with the ability of Bcl-2, Bcl-XL, and Bax to form pores in synthetic membranes, suggest that they may exert their influence through pore-forming activities in intracellular membranes, particularly mitochondrial membranes. Bcl-2 family members may regulate apoptosis by changing the permeability of membranes to ions and apoptosis-inducing molecules, and physical interactions between Bcl-2 family proteins mediated by the BH domains may be important in both pore-forming and pore-inhibiting activities. Research findings suggest that the levels of Bcl-2 family members in B-CLL cells may be modulated by a wide range of largely extracellular influences, including the cytokines interleukin-4 (IL-4), IL-8, IL-10, interferon-a (IFN-?), IFN-?, and basic fibroblast growth factor (bPGF). Levels of Bcl-2 family members may also be modulated by contact between B-CLL cells and bone marrow (BM) stromal cells, activation of lgM, CD95, CD40 or CD6, the p53 gene product, and co-cultivation with CDw32-transfected murine fibroblasts. Such modulation may offer some insight into the pathogenesis of the disease, an explanation for the higher level expression of Bcl-2 family members in B-CLL, and an explanation for the highly variable prognosis. Additionally, if Bcl-2 family members can be shown unequivocally to be controlled by any of these molecular entities, the existence of these influences may offer the opportunity to reduce the neoplastic cells' apoptotic threshold by manipulating the relative levels of pro- and anti-apoptotic Bcl-2 family members as a treatment regime, or prior to more conventional treatment regimes.