Expression of bcl2 family proteins and active caspase 3 in classical Hodgkin's lymphomas.

The expression of various bcl2 family proteins has been reported in Hodgkin and Reed-Sternberg cells, but the proteins bad, bid, and bim have not been analyzed in classical Hodgkin's lymphomas (HLs). This study aimed to investigate the expression of the proteins bcl2, bcl-xl, mcl1, bax, bak, bad, bid, bim, and active caspase 3, and the TUNEL (terminal deoxynucleotidyl transferase-mediated in situ labeling) index to gain further insight into the apoptosis profile of classical HLs. A high expression of the proteins bcl2, bcl-xl, mcl1, bax, bak, bad, bid, and bim in HRS cells was found in 27 of 101 (27%), 95 of 101 (94%), 27 of 97 (29%), 73 of 95 (77%), 37 of 102 (36%), 85 of 94 (90%), 19 of 109 (17%), and 43 of 91 (47%) cases, respectively. The high expression of bcl-xl, bax, and bad in HRS cells in most classical HLs indicates that these proteins may play predominant roles in the regulation of apoptosis in classical HLs. Active caspase 3-positive and TUNEL-positive Reed-Sternberg cells were detected in 47 of 70 (67%; range, 0%-12%) and 60 of 71 (85%; range, 0%-19%) cases, respectively. Significant positive correlations were found between bax/bcl2 (P = .002), bad/bcl2 (P = .020), bad/bcl-xl (P = .003), and bim/mcl1 (P = .036). Based on these findings, it could be hypothesized that the antiapoptotic proteins bcl2, bcl-xl, and mcl1 may counteract the expression of the proapoptotic proteins bax, bad, and bim, thereby contributing to the survival of Reed-Sternberg cells.

Diffuse large B-cell lymphomas with germinal center B-cell-like differentiation immunophenotypic profile are associated with high apoptotic index, high expression of the proapoptotic proteins bax, bak and bid and low expression of the antiapoptotic protein bcl-xl.

The aim of this study was to analyze the relations between differentiation immunophenotypes and the status of apoptosis and proliferation in diffuse large B-cell lymphomas. Therefore, the bcl6/CD10/MUM1/CD138 differentiation immunophenotypic profiles were studied in relation to (a) the apoptotic index, (b) the apoptosis-associated bcl2 family proteins bcl2, bcl-xl, bax, bak, bad and bid, (c) the proliferation index (Ki67) and (d) the cell cycle proteins cyclin A, cyclin B1, cyclin D3, cyclin E, p53, Rb, p16 and p27 in 79 cases of diffuse large B-cell lymphomas. Two major differentiation immunophenotypic profiles were distinguished: the germinal center B-cell-like profile; 31 cases (bcl6+/CD10+/-/MUM1-/CD138-: 29 cases and bcl6-/CD10+/MUM1-/CD138-: two cases) and the nongerminal center B-cell-like profile (bcl6+/-/CD10-/MUM1+/CD138-); 48 cases. The expression of bax, bak and bid and the apoptotic index were significantly higher in the germinal center B-cell-like profile than in the nongerminal center B-cell-like profile (P=0.045, 0.018, 0.003 and 0.034, respectively). In contrast, the expression of bcl-xl was significantly lower in the germinal center B-cell-like profile than in the nongerminal center B-cell-like profile (P=0.026). The expression of bcl6 and CD10 showed significant positive correlation with the expression of bax (r=0.659, P<0.001 and r=0.240, P=0.033, respectively), bak (r=0.391, P<0.001 and r=0.233, P=0.039, respectively) and bid (r=0.652, P<0.001 and r=0.238, P=0.035, respectively) and significant negative correlation with the expression of bcl-xl (r=-0.536, P<0.001 and r=-0.250, P=0.029, respectively). The expression of MUM1 showed significant negative correlation with the expression of bax (r=-0.276, P=0.014) and bid (r=-0.266, P=0.018) and significant positive correlation with the expression of bcl-xl (r=0.238, P=0.037). The above findings indicate that diffuse large B-cell lymphomas with germinal center B-cell-like immunophenotypic profile are associated with increased apoptosis status, high expression of the proapoptotic proteins bax, bak and bid and low expression of the antiapoptotic protein bcl-xl.

Proliferation profile of classical Hodgkin's lymphomas. Increased expression of the protein cyclin D2 in Hodgkin's and Reed-Sternberg cells.

There is accumulating evidence that Hodgkin's and Reed-Sternberg cells of classical Hodgkin's lymphomas (cHL) display multiple and concurrent alterations in different pathways and checkpoints of the cell cycle. However, the expression of cyclin D2 and its relation to other major cell cycle proteins has not been analyzed in cHL. The aim of the present study was to assess expression of cyclin D2, Ki67, cyclin A, cyclin B1, cyclin D1, cyclin D3, cyclin E, p53, Rb, p16 and p27 proteins in order to gain further insight into the proliferation profile of cHL. Overexpression of cyclin D2 in Hodgkin's and Reed-Sternberg cells was detected in 64/89 (72%) cases of cHL. This finding, in view of recent in vitro data showing that constitutive activation of nuclear factor (NF)-kB could upregulate cyclin D2 expression in part via signal transducer and activator of transcription (STAT)-5a, suggests that induction of cyclin D2 expression may support the proliferation of Hodgkin's and Reed-Sternberg cells. In addition, the present study showed that (1) increased p27 expression status was significantly correlated with higher levels of cyclin A expression (P=0.048) and (2) increased p53 expression status was significantly correlated with higher levels of cyclin A (P<0.001) and cyclin B1 (P=0.040) expression. The association between increased p27 and p53 expression status and higher expression levels of G2/M cyclins suggests that the impairment of the growth inhibitory activity of the p27 and p53 tumor suppressor pathways may promote the proliferation of Hodgkin's and Reed-Sternberg cells.