M'kacher R, Bennaceur A, Farace F, Laugé A, Plassa L F, Wittmer E, Dossou J, Violot D, Deutsch E, Bourhis J, Stoppa-Lyonnet D, Ribrag V, Carde P, Parmentier C, Bernheim A, Turhan A G
Department of Medicine, UPRES EA 27-10, Villejuif, France.
Oncogene. 2003 Sep 11;22(39):7905-12. doi: 10.1038/sj.onc.1206826.
Mantle cell lymphomas (MCL) are characterized by their aggressive behavior and poor response to chemotherapy regimens. We report here evidence of increased in vitro radiation sensitivity in two cell lines that we have generated from two MCL patients (UPN1 and UPN2). However, despite their increased radiation sensitivity, UPN2 cells were totally resistant to apoptotic cell death, whereas UPN1 cells underwent massive apoptosis 6 h after irradiation. The frequency of induced chromosomal abnormalities was higher in UPN1 as compared to UPN2. Distinct mechanisms have been found to contribute to this phenotype: a major telomere shortening (UPN1 and UPN2), deletion of one ATM allele and a point mutation in the remaining allele in UPN2, mutation of p53 gene (UPN1 and UPN2) with absence of functional p53 as revealed by functional yeast assays. After irradiation, Ku70 levels in UPN1 increased and decreased in UPN2, whereas in the same conditions, DNA-PKcs protein levels decreased in UPN1 and remained unchanged in UPN2. Thus, irradiation-induced apoptotic cell death can occur despite the nonfunctional status of p53 (UPN1), suggesting activation of a unique pathway in MCL cells for the induction of this event. Overall, our study demonstrates that MCL cells show increased radiation sensitivity, which can be the result of distinct molecular events. These findings could clinically be exploited to increase the dismal response rates of MCL patients to the current chemotherapy regimens.
套细胞淋巴瘤（MCL）的特点是具有侵袭性且对化疗方案反应不佳。我们在此报告，我们从两名MCL患者（UPN1和UPN2）中培养出的两个细胞系显示出体外辐射敏感性增加的证据。然而，尽管UPN2细胞的辐射敏感性增加，但它们对凋亡性细胞死亡完全耐药，而UPN1细胞在照射后6小时发生大量凋亡。与UPN2相比，UPN1中诱导的染色体异常频率更高。已发现不同机制导致了这种表型：主要的端粒缩短（UPN1和UPN2），UPN2中一个ATM等位基因缺失且另一个等位基因存在点突变，p53基因发生突变（UPN1和UPN2），功能性酵母试验显示缺乏功能性p53。照射后，UPN1中的Ku70水平升高而UPN2中降低，而在相同条件下，UPN1中的DNA-PKcs蛋白水平降低而UPN2中保持不变。因此，尽管p53处于无功能状态（UPN1），照射诱导的凋亡性细胞死亡仍可发生，这表明MCL细胞中存在一种独特的途径来诱导这一事件。总体而言，我们的研究表明MCL细胞显示出增加的辐射敏感性，这可能是不同分子事件的结果。这些发现可在临床上加以利用，以提高MCL患者对当前化疗方案的惨淡反应率。
