Bleomycin induces short-term telomere fragility in Epstein-Barr virus-transformed human lymphoblastoid cells

Abstract

The induction of telomere dysfunction-related chromosomal aberrations by the radiomimetic antibiotic bleomycin(BLM) was studied in human lymphoblastoid cells immortalized with the Epstein-Barr virus (EBV). To thisend, an EBV-induced lymphoblastoid cell line (T-37) was exposed to increased concentrations of BLM (10–100µg/mL) for 2 h at 37ºC, and telomere aberrations were analyzed 24 h (first mitosis) after treatment using PNA-FISH with pan-telomeric plus pan-centromeric probes. Telomere signal duplications (TSD) increased significantlyin BLM-exposed cells (p < 0.01), although the concentration-response relationship was non-linear. Most of theinduced TSD (95–99 %) were of chromatid-type. No induction of telomere signal loss, telomere fusions ortelomere associations by BLM was observed in T-37 cells. These findings show that BLM induces short-termtelomere dysfunction in EBV-transformed human lymphoblastoid cells in the form of TSD (which implies telomerefragility) and suggest that these effects mainly occur during the G2 stage of the cell cycle. The persistence ofthis type of aberrations in the long-term in EBV-induced lymphoblastoid cells and other human cells exposed toBLM may be of medical relevance. Telomere fragility induced by BLM could promote genomic instability, whichmight contribute to the development of secondary tumors in patients undergoing chemotherapy based on thiscompound. Consequently, our study raises concerns about the potential long-term genomic effects of BLM intreated patients and suggests that the analysis of TSD could be a useful biomarker for detecting BLM-inducedtelomere dysfunction in human cells.