Expression of Apoptosis-Regulating Proteins in Chronic Lymphocytic Leukemia: Correlations With In Vitro and In Vivo Chemoresponses

Abstract

B-cell chronic lymphocytic leukemia (B-CLL) represents a neoplastic disorder caused primarily by defective programmed cell death (PCD), as opposed to increased cell proliferation. Defects in the PCD pathway also contribute to chemoresistance. The expression of several apoptosis-regulating proteins, including the Bcl-2 family proteins Bcl-2, Bcl-XL, Mcl-1, Bax, Bak, and BAD; the Bcl-2–binding protein BAG-1; and the cell death protease Caspase-3 (CPP32), was evaluated by immunoblotting using 58 peripheral blood B-CLL specimens from previously untreated patients. Expression of Bcl-2, Mcl-1, BAG-1, Bax, Bak, and Caspase-3 was commonly found in circulating B-CLL cells, whereas the Bcl-XL and BAD proteins were not present. Higher levels of the anti-apoptotic protein Mcl-1 were strongly correlated with failure to achieve complete remission (CR) after single-agent therapy (fludarabine or chlorambucil) (P = .001), but the presence of only seven CRs among the 42 patients for whom follow-up data were available necessitates cautious interpretation of these observations. Higher levels of the anti-apoptotic protein BAG-1 were also marginally associated with failure to achieve CR (P = .04). Apoptosis-regulating proteins were not associated with patient age, sex, Rai stage, platelet count, hemoglobin (Hb) concentration, or lymph node involvement, although higher levels of Bcl-2 and a high Bcl-2:Bax ratio were correlated with high numbers (>105/μL) of white blood cells (WBC) (P = .01; .007) and higher levels of Bak were weakly associated with loss of allelic heterozygosity at 13q14 (P = .04). On the basis of measurements of apoptosis induction by fludarabine using cultured B-CLL specimens, in vitro chemosensitivity data failed to correlate with in vivo clinical response rates (n = 42) and expression of the various apoptosis-regulating proteins. Although larger prospective studies are required before firm conclusions can be reached, these studies show the expression in B-CLLs of multiple apoptosis-regulating proteins and suggest that the relative levels of some of these, such as Mcl-1, may provide information about in vivo responses to chemotherapy. In vitro chemosensitivity data, however, do not appear to be particularly useful in predicting responses in B-CLL.

Apoptosis and leukaemia

“…The ratio of Bcl-2 to Bax correlates inversely with the sensitivity of B-CLL cells to cytotoxic drugs in vitro. However, in vitro sensitivity to fludarabine failed to correlate with the achievement of clinical response (Kitada et al, 1998). CLL cells show an extended lifespan in vivo.…”

Phenol red reduces ROSC mediated cell cycle arrest and apoptosis in human MCF‐7 cells

“…]. The dysfunction of apoptotic processes occurring in some types of malignant diseases such as lymphoma or B-CLL leukaemia is closely related to the overexpression of prosurvival proteins such as Bcl-2, survivin or Mcl-1 [Kitada et al, 1998;Hahntow et al, 2004;Stankovic et al, 2004;Alvi et al, 2005]. These observations illustrate the importance of the pro-apoptotic action of ROSC.…”

CD40 stimulation of B‐cell chronic lymphocytic leukaemia cells enhances the anti‐apoptotic profile, but also Bid expression and cells remain susceptible to autologous cytotoxic T‐lymphocyte attack

“…B-cell chronic lymphocytic leukaemia (B-CLL) is considered as a prime example of malignancy involving defects in cell death regulation. This results in relative chemoresistance (Kitada et al, 1998), making this disease currently incurable. As B-CLL is characterized by a slow accumulation rate, allowing time for the generation of an immune response against the tumour cells, it is an attractive disease for immunotherapeutic approaches.…”