DNA polymerase ν gene expression influences fludarabine resistance in chronic lymphocytic leukemia independently of p53 status
| Autor: | Srdana Grgurevic, Patricia Montilla-Perez, Alice Bradbury, Julia Gilhodes, Sophie Queille, Sandrine Pelofy, Aurélien Bancaud, Thomas Filleron, Loïc Ysebaert, Christian Récher, Guy Laurent, Jean-Jacques Fournié, Christophe Cazaux, Anne Quillet-Mary, Jean-Sébastien Hoffmann |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Haematologica, Vol 103, Iss 6 (2018) |
| Druh dokumentu: | article |
| ISSN: | 0390-6078 1592-8721 |
| DOI: | 10.3324/haematol.2017.174243 |
| Popis: | Alteration in the DNA replication, repair or recombination processes is a highly relevant mechanism of genomic instability. Despite genomic aberrations manifested in hematologic malignancies, such a defect as a source of biomarkers has been underexplored. Here, we investigated the prognostic value of expression of 82 genes involved in DNA replication-repair-recombination in a series of 99 patients with chronic lymphocytic leukemia without detectable 17p deletion or TP53 mutation. We found that expression of the POLN gene, encoding the specialized DNA polymerase ν (Pol ν) correlates with time to relapse after first-line therapy with fludarabine. Moreover, we found that POLN was the only gene up-regulated in primary patients’ lymphocytes when exposed in vitro to proliferative and pro-survival stimuli. By using two cell lines that were sequentially established from the same patient during the course of the disease and Pol ν knockout mouse embryonic fibroblasts, we reveal that high relative POLN expression is important for DNA synthesis and cell survival upon fludarabine treatment. These findings suggest that Pol ν could influence therapeutic resistance in chronic lymphocytic leukemia. (Patients’ samples were obtained from the CLL 2007 FMP clinical trial registered at: clinicaltrials.gov identifer: 00564512). |
| Databáze: | Directory of Open Access Journals |
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