The functional evaluation of
ataxia telangiectasia mutated (ATM) and p53 was recently developed in
B-cell chronic lymphocytic leukaemia (B-CLL), a disease in which the response to
DNA damage is frequently altered. We identified a novel biomarker of
chemosensitivity based on the induction of
DNA damage by the
purine nucleoside analogues (PNA)
fludarabine and
2-chlorodeoxyadenosine (CdA). Using genome-wide expression profiling, it was observed that, in chemosensitive samples, PNA predominantly increased the expression of p53-dependent genes, among which
PLK2 was the most highly activated at early time points. Conversely, in chemoresistant samples, p53-dependent and
PLK2 responses were abolished. Using a quantitative real time
polymerase chain reaction, we confirmed that PNA dose- and time-dependently increased
PLK2 expression in chemosensitive but not chemoresistant B-CLL samples. Analysis of a larger cohort of B-CLL patients showed that
cytotoxicity induced by PNA
correlated well with
PLK2 mRNA induction. Interestingly, we observed that failure to up-regulate
PLK2 following PNA and chemoresistance were not strictly
correlated with structural alterations in the
TP53 gene. In conclusion, we propose that testing
PLK2 activation after a 24-h incubation with PNA could be used to investigate the functional integrity of
DNA damage-response pathways in B-CLL cells, and predict clinical sensitivity to these
drugs.
