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

Br J Haematol. 2009 Dec;147(5):641-52. doi: 10.1111/j.1365-2141.2009.07900.x. Epub 2009 Sep 18.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacology*
  • Biomarkers, Tumor / biosynthesis*
  • Biomarkers, Tumor / genetics
  • Cell Death / drug effects
  • Cladribine / pharmacology
  • Cohort Studies
  • DNA Damage
  • DNA, Neoplasm / genetics
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Enzymologic / drug effects
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / enzymology*
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Male
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis / methods
  • Protein-Serine-Threonine Kinases / biosynthesis*
  • Protein-Serine-Threonine Kinases / genetics
  • RNA, Messenger / genetics
  • RNA, Neoplasm / genetics
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Tumor Cells, Cultured
  • Up-Regulation / drug effects*
  • Vidarabine / analogs & derivatives
  • Vidarabine / pharmacology

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • DNA, Neoplasm
  • RNA, Messenger
  • RNA, Neoplasm
  • Cladribine
  • PLK2 protein, human
  • Protein-Serine-Threonine Kinases
  • Vidarabine
  • fludarabine