CLL is a human malignancy caused principally by defects that prevent programmed cell death rather than by alterations in cell cycle regulation. In the vast majority of patients, CLL cells are predominantly G0 quiescent cells that gradually accumulate in the patient's body, not because they are dividing more rapidly than normal, but because they are surviving too long. Several methods have been used to evaluate tumor cell proliferation and to correlate kinetic cellular parameters with clinical features and outcome. One of the first and most useful methods of evaluating cell proliferation is the analysis of lymphocyte doubling time (LDT), defined as the time needed to double the peripheral blood lymphocyte count (64,65). Montserrat et al. (64) analyzed the LDT in 100 untreated patients with CLL. LDT was investigated in relation to clinical stages, bone marrow histological patterns, treatment-free period, and survival. Although it was partially correlated with clinical stages and bone marrow pattern, LDT was shown to have a clear prognostic significance by itself. Thus, whereas an LDT of 12 or fewer months identified a population of patients with poor prognosis, an LDT of higher than 12 mo was indicative of good prognosis, as substantiated by long treatment-free periods and survival. Because of its simplicity, LDT constitutes a largely accepted parameter for assessing the pace of disease development (64,66).
Other methods have been used to correlate tumor cell proliferation with clinical outcome. Cordone et al. (67) analyzed the frequency and clinical significance of Ki-67+ cells in patients with CLL. The percentage and absolute number of Ki-67+ leukemic cells was found to be higher in advanced stages of the disease and also correlated with the proportion of prolymphocytes. Moreover, Ki-67 identified patients with more aggressive forms of CLL and Richter's syndrome, in which all the large lymphoma cells were Ki-67+. On the other hand, Del Giglio et al. (68) focused on the expression of proliferating cell nuclear antigen (PCNA), a 36-Kda nuclear protein, the regulation of which is cell cycle-dependent. In CLL, PCNA levels correlated with cell proliferation, clinical stage, and the LDT. Interestingly, low PCNA levels were predictive of a response to fludarabine. Orfao et al. (69) analyzed the proliferation rate of peripheral blood (PB) lymphocytes from CLL patients, as expressed by the absolute PB S-phase leukocyte count. This parameter was related to other clinical and biological factors. Taken independently, it is also an important variable in predicting early death in CLL (69).
Other molecules related to cell cycle regulation have been studied. Thus, p27k protein, a cyclin-dependent kinase inhibitor, was studied in B-CLL patients. As expected, increased levels of p27k protein correlated with LDT (70). Moreover, survival of patients with increased expression of p27 was shorter than in those with low p27k expression (70). In addition, although overexpression of cyclin D1 is a specific marker of mantle-cell lymphoma (71,72), some sporadic cases with aggressive behavior overexpress cyclin D1 (73).
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