DNA polymerase ν gene expression influences fludarabine resistance in chronic lymphocytic leukemia independently of p53 status.
Haematologica
; 103(6): 1038-1046, 2018 06.
Article
en En
| MEDLINE
| ID: mdl-29567785
ABSTRACT
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).
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Vidarabina
/
Leucemia Linfocítica Crónica de Células B
/
Regulación Leucémica de la Expresión Génica
/
Proteína p53 Supresora de Tumor
/
Resistencia a Antineoplásicos
/
ADN Polimerasa Dirigida por ADN
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Año:
2018
Tipo del documento:
Article