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Chlorambucil resistance in B‐cell chronic lymphocytic leukaemia is mediated through failed Bax induction and selection of high Bcl‐2‐expressing subclones

Our previous data have shown that high Bcl‐2/Bax ratios in chronic lymphocytic leukaemia (B‐CLL) correlate with in vitro apoptosis and clinical resistance. We have now monitored the in vitro viability of B‐CLL cells in relation to Bcl‐2 and Bax expression over a 48 h time course following exposure to chlorambucil. The results showed that Bax up‐regulation was essential for chlorambucil‐induced apoptosis in B‐CLL cells and a 3‐fold increase in expression within 4 h of exposure to drug was typically observed in sensitive cells; resistant cells failed to up‐regulate Bax at all. In contrast, the constitutively high levels of Bcl‐2 found in B‐CLL cells were found to be down‐regulated in apoptotic cells but the mean Bcl‐2 expression in viable cells was increased, probably as a result of the loss of lower Bcl‐2‐expressing cells into the apoptotic compartment. Taken together, these data add further weight to the suggestion that Bcl‐2/Bax ratios may be pivotal in determining the fate of B‐CLL cells. Furthermore, the Bcl‐2/Bax ratios found in apoptotic B lymphocytes were remarkably similar in the treated, untreated and normal control cells, which suggests that there is a universal Bcl‐2/Bax ratio threshold for cell survival and cell death.