Premium
Impaired up‐regulation of polo‐like kinase 2 in B‐cell chronic lymphocytic leukaemia lymphocytes resistant to fludarabine and 2‐chlorodeoxyadenosine: a potential marker of defective damage response
Author(s) -
De Viron Emeline,
Knoops Laurent,
Connerotte Thierry,
Smal Caroline,
Michaux Lucienne,
Saussoy Pascale,
Vannuffel Pascal,
Beert Eline,
Vekemans MarieChristiane,
Hermans Cédric,
Bontemps Françoise,
Van Den Neste Eric
Publication year - 2009
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2009.07900.x
Subject(s) - fludarabine , chronic lymphocytic leukemia , dna damage , cancer research , dna repair , biology , deoxycytidine kinase , microbiology and biotechnology , leukemia , gene , dna , immunology , biochemistry , genetics , deoxycytidine , chemotherapy , gemcitabine , cyclophosphamide
Summary 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.