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Multiple molecular mechanisms contribute to radiation sensitivity in mantle cell lymphoma

Oncogene volume 22, pages 7905–7912 (2003)Cite this article

Abstract

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.

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Acknowledgements

We thank Pr H de Thé (Laboratoire de biochimie B, Hopital Saint-Louis, Paris) for p53 investigation, Dr N Andersen (Department of Hematology, Copenhagen, Denmark) for providing MCL cell lines (Granta and NCE) and Dr M Gueret-Amor for providing AT cell line. We also thank ML Bonnet and M Guillier for their excellent technical help.

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Authors and Affiliations

  1. Translational Research-Cell Therapy Laboratory, Inserm, Villeujuif, U362, France

    A Bennaceur, F Farace, V Ribrag & A G Turhan

  2. Departments of Medicine, Clinical Biology, UPRES EA 27-10, Villejuif, France

    R M'kacher, A Bennaceur, F Farace, J Dossou, D Violot, E Deutsch, J Bourhis, V Ribrag, P Carde, C Parmentier & A G Turhan

  3. Cytogenetic and Oncologic Genetic Laboratory, IGR, Villejuif, France

    A Bernheim

  4. Service de Genetique Oncologique, Institut Curie, France

    A Laugé & D Stoppa-Lyonnet

  5. Laboratoire de Biochimie B, Hospital St Louis, Paris, France

    L F Plassa & E Wittmer

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  1. R M'kacher
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  15. A Bernheim
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Correspondence to A G Turhan.

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M'kacher, R., Bennaceur, A., Farace, F. et al. Multiple molecular mechanisms contribute to radiation sensitivity in mantle cell lymphoma. Oncogene 22, 7905–7912 (2003). https://doi.org/10.1038/sj.onc.1206826

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