As mentioned above, the proliferative capacity of classical CLL is low, and the leukemic cells expand mainly because of a prolonged life span caused by a dysregulation of apoptosis. Both intrinsic and extrinsic cellular factors have been held responsible for this abnormality.
The progressive expansion of CLL in the face of its poor proliferative capacity has led to the notion that the neoplastic cells in this disease enjoy increased longevity owing to defective apoptosis rather than to alterations in cell cycle regulation. Apoptosis, or programmed cell death, consists of a cascade of biochemical events leading to cell destruction that plays a critical role both in normal tissue development and in malignancy (83). The apoptotic failure of CLL has been studied extensively, and numerous mechanisms have been proposed to explain this deficiency. Of course, most investigations have been centered on the Bcl-2 gene family and their proteins (84-86). The importance of the anti-apoptosis Bcl-2 oncogene in B-cell malignancies was established more than 20 years ago in follicular lymphomas with the t(14;18). However, in contrast to follicular lymphomas, translocations of the Bcl-2 gene are relatively infrequent in CLL (87). Indeed, unlike other B-cell lymphoproliferative disorders, CLL is not associated with specific molecular defects, although many show deletions of the long arm of chromosome 13 or trisomy 12, possibly deregulating genes encoding for proteins involved in apoptosis (88). Despite the infrequent Bcl-2 gene rearrangements, high expression of Bcl-2 mRNA and protein are quite common in CLL (89,90). Apparently, the mechanism of bcl-2 overexpression in CLL is not owing to gene rearrangement, but rather to hypomethylation of Bcl-2 promoter region DNA (90). Bcl-2 is only one member of a large family of apoptosis-regulating proteins. Some of these proteins function like Bcl-2 as inhibitors of apoptosis, whereas others are cell death promoters. The level of expression of apoptosis-related genes other than Bcl-2 was also investigated in CLL. Elevated BCL-2 and Bax expression was associated with apoptosis resistance (91). Gottardi et al. (85) detected high message and protein Bax expression in most B-CLL cases. They also showed high levels of Bcl-xL in many but not all cases, whereas Bcl-xS was detectable only in very low amounts in some patients, a pattern that is skewed toward prevention of apoptosis. Similarly, Krajewski et al. (92), using specific antibodies, showed that Bcl-2, Mcl-1, Bax, Bak, BAG-1, and Caspase-3 were commonly expressed in circulating B-CLLs, whereas the Bcl-X and BAD proteins were not present at detectable levels.
Some studies suggest that Bax is the critical protein in determining the fate of CLL cells following apoptotic signals and that Bcl-2 and Bax interaction, rather than the absolute level of Bcl-2 expression, is a more important determinant of B-CLL cell apoptosis (93). In this regard it was shown that levels of Bcl-2 correlate with those of the pro-apoptotic protein Bax (86).
The fact that despite their prolonged survival in vivo, a substantial proportion of CLL cells only survive a few days when cultured in vitro has intrigued investigators (94). This observation has prompted the notion that the genetic abnormalities of the CLL cell do not entirely account for all aspects of cell accumulation, which may also be influenced by external stimuli. Numerous studies have shown that host elements extrinsic to the neoplastic cells may provide survival signals to the neoplastic cells in vivo. When these elements are absent, i.e., in culture, CLL cells have the propensity to undergo spontaneous apoptosis. These survival factors in CLL would include cytokines and soluble molecules, such as interferon-a and -y, interleukin-2, -4, -6, -8, and -13 (95-100), the ligand for 02 integrins (101), tumor necrosis factor-a (102), immune complexes in the context of accessory leukocytes (103), inflammatory elements such as CD40 ligand (CD154) (104). and antigen for which the malignant clone has affinity (105).
At the cellular level, receptor abnormalities may contribute to the long-lived status of B-CLL cells. For example, B-CLL cells show a defective CD40-mediated signal transduction and a downregulated expression of the apoptosis-inducer CD95 (Fas). As a consequence, no apoptosis could be induced in B-CLL cells by a soluble anti-CD95 monoclonal antibody (106). Also, perturbed T-cell/B-cell interactions have been described in this disease (107).
A large body of experimental data emphasizes the protective role of the stromal microenvironment that exerts a strong influence in vivo on the promotion of progressive accumulation of the CLL cell (108). Cell-to-cell and matrix interactions mediated by adhesion molecules prevent the death of B-CLL cells (94). Also, B-CLL cell-to-matrix binding results in an increased Bcl-2/Bax ratio and prevents apoptosis (109). Binding of stromal cells from bone marrow to B-CLL cells was shown to prevent B-CLL apoptotic cell death in vitro (110,111). Blood-derived "nurse-like" cells also show similar effects (112). These studies suggest that direct cell-to-cell contact and/or cell-to-matrix- or membrane-bound cytokines rather than soluble factors may be important for the in vivo survival of CLL cells.
The role of apoptosis and cell kinetics in CLL progression were investigated by Ricciardi et al. (113), who observed that CLL cells from patients with progressive disease were more quiescent and exhibited much lower susceptibility to apoptosis than those from patients with stable disease, even in the presence of autologous serum. These investigators speculated that higher quiescence may be responsible for the decreased susceptibility of cells from patients with progressive disease to enter apoptosis. The clinical impact of apoptotic-related gene expression has also been investigated. High Bcl-2 levels have been associated with the presence of adverse prognostic factors (114). Kitada et al. (115) studied a large number of Bcl-2 family proteins including Bcl-2, Bcl-XL, Mcl-1, Bax, Bak, Baf, the Bcl-2 binding protein Bag-1, and the protease caspase-3 with regard to therapy response. These authors found that overexpression of the Mcl-1 protein was strongly associated with lower patient response rate.
Another gene implicated in the regulation of cell cycle arrest and apoptosis is p53, a tumor suppressor gene that is commonly mutated in a variety of human cancers (116). A large study demonstrated that p53 mutations in CLL correlate with a much higher frequency of disease progression, inferior survival, and poor response to therapy (117).
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