Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
PLoS One. 2013 Jul 29;8(7):e70428. doi: 10.1371/journal.pone.0070428. Print 2013.
We report that Imetelstat, a telomerase inhibitor that binds to the RNA component of telomerase (hTR), can sensitize primary CLL lymphocytes to fludarabine in vitro. This effect was observed in lymphocytes from clinically resistant cases and with cytogenetic abnormalities associated with bad prognosis. Imetelstat mediated-sensitization to fludarabine was not associated with telomerase activity, but with the basal expression of Ku80. Since both Imetelstat and Ku80 bind hTR, we assessed 1) if Ku80 and Imetelstat alter each other's binding to hTR in vitro and 2) the effect of an oligonucleotide complementary to the Ku binding site in hTR (Ku oligo) on the survival of primary CLL lymphocytes exposed to fludarabine. We show that Imetelstat interferes with the binding of Ku70/80 (Ku) to hTR and that the Ku oligo can sensitize CLL lymphocytes to FLU. Our results suggest that Ku binding to hTR may contribute to fludarabine resistance in CLL lmphocytes. This is the first report highlighting the potentially broad effectiveness of Imetelstat in CLL, and the potential biological and clinical implications of a functional interaction between Ku and hTR in primary human cancer cells.
我们报告称，结合端粒酶 RNA 成分（hTR）的端粒酶抑制剂依美替司他可使慢性淋巴细胞白血病（CLL）原代淋巴细胞对氟达拉滨敏感。该作用在临床上耐药的病例以及与预后不良相关的细胞遗传学异常的淋巴细胞中观察到。依美替司他介导的氟达拉滨敏感性与端粒酶活性无关，而是与 Ku80 的基础表达有关。由于依美替司他和 Ku80 均结合 hTR，我们评估了 1）依美替司他和 Ku80 是否在体外相互影响彼此与 hTR 的结合，以及 2）Ku 结合位点互补寡核苷酸（Ku oligo）对暴露于氟达拉滨的原代 CLL 淋巴细胞存活的影响。我们发现依美替司他干扰 Ku70/80（Ku）与 hTR 的结合，并且 Ku oligo 可使 CLL 淋巴细胞对 FLU 敏感。我们的结果表明，Ku 与 hTR 的结合可能导致 CLL 淋巴细胞对氟达拉滨产生耐药性。这是首次报道强调了依美替司他在 CLL 中潜在的广泛有效性，以及 Ku 和 hTR 之间的功能相互作用在原发性人类癌细胞中的生物学和临床意义。
