DNA polymerase ν gene expression influences fludarabine resistance in chronic lymphocytic leukemia independently from p53 status
Résumé
Alteration in the DNA Replication, Repair or Recombination processes is a highly relevant mechanism of genomic instability. Despite genomic aberrations manifested in haematological malignancies, such a defect as a source of biomarkers has been underexplored. Here, we investigated prognostic value of expression of 82 genes involved in DNA Replication-Repair-Recombination in a series of 99 patients with chronic lymphocytic leukaemia without detected 17p deletion or TP53 mutation. We unveiled that expression of the POLN gene, encoding the specialized DNA polymerase ν (Polν) correlates with time to relapse after the first-line therapy with fludarabine. Moreover, we found that POLN was the only gene upregulated in primary patient lymphocytes when exposed in vitro to proliferative and prosurvival stimuli. By using 2 cell lines that were sequentially established from the same patient during the course of the disease and Polν knockout mouse embryonic fibroblasts, we reveal that relative high POLN expression is important for DNA synthesis and cell survival upon fludarabine treatment. These findings suggest that Polν could influence therapeutic resistance in chronic lymphocytic leukemia.