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Inactivation of the ARF–MDM-2–p53 pathway in sporadic Burkitt's lymphoma in children

Leukemia volume 18, pages 584–588 (2004)Cite this article

Abstract

Burkitt's lymphomas (BLs) are characterized by an activated MYC gene that provides a constitutive proliferative signal. However, activated myc can initiate ARF-dependent activation of p53 and apoptosis as well. Data derived from cell culture and animal models suggest that the inactivation of the ARF–MDM-2–p53 apoptotic signaling pathway may be a necessary secondary event for the development of BL. This has not been tested in freshly excised BL tissue. We investigated the ARF–MDM-2–p53 pathway in tumor specimen from 24 children with sporadic BL/B-ALL. Direct sequencing revealed a point mutation in the p53 gene in four BL. Overexpression of MDM-2 was evident in 10 of the BL samples analyzed by real-time quantitative PCR. Deletion of the CDKN2A locus that encodes ARF or reduced expression of ARF could not be detected in any BL by fluorescence in situ hybridization analysis or real-time quantitative PCR, respectively. Our results indicate that the ARF–MDM-2–p53 apoptotic pathway is disrupted in about 55% of the cases of childhood sporadic BL. We suggest that in addition to the inactivation of the ARF–MDM-2–p53 protective checkpoint function other antiapoptotic mutations may occur in a substantial part of children with sporadic BL.

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Acknowledgements

We thank Dr WD Ludwig (Berlin, Germany) for providing frozen bone marrow or tumor tissue. Simone Schwalm and Steffanie Garkisch provided expert technical assistance. This work was supported by the McDonalds Kinderhilfe and the Forschungshilfe Station Peiper.

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Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, Justus-Liebig-University, Giessen, Germany

    M Wilda, J Bruch, A Reiter, A Borkhardt & W Woessmann

  2. Department of Human Genetics, University Hospital Kiel, Kiel, Germany

    L Harder

  3. Department of Pediatric Cardiology, Justus-Liebig-University, Giessen, Germany

    D Rawer

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  1. M Wilda
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  2. J Bruch
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Correspondence to W Woessmann.

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Wilda, M., Bruch, J., Harder, L. et al. Inactivation of the ARF–MDM-2–p53 pathway in sporadic Burkitt's lymphoma in children. Leukemia 18, 584–588 (2004). https://doi.org/10.1038/sj.leu.2403254

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