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p14ARF homozygous deletion or MDM2 overexpression in Burkitt lymphoma lines carrying wild type p53

Oncogene volume 20, pages 2171–2177 (2001)Cite this article

Abstract

The hallmark of Burkitt lymphoma (BL) is a constitutively activated c-myc gene that drives tumor cell growth. A majority of BL-derived cell lines also carry mutant p53. In addition, the p16INK4a promoter is hypermethylated in most BL biopsies and BL cell lines, leading to silencing of this gene. Activation of c-myc and/or cell cycle dysregulation can induce ARF expression and p53-dependent apoptosis. We therefore investigated the p14ARF-MDM2-p53 pathway in BL cell lines. p14ARF was expressed and localized to nucleoli in all BL carrying mutant p53. Three out of seven BL carrying wt p53 had a homozygous deletion of the CDKN2A locus that encodes both p14ARF and p16INK4a. Three BL carrying wild type p53 retained the CDKN2A locus and overexpressed MDM2. DNA sequencing revealed a point mutation in CDKN2A exon 2 in one of these BL, Seraphine. However, this point mutation did not affect p14ARF's nucleolar localization or ability to induce p53. The Bmi-1 protein that negatively regulates the p14ARF promoter and co-operates with c-myc in tumorigenesis was expressed at low to moderate levels in all BL analysed. Our results indicate that inactivation of the ARF-MDM2-p53 pathway is an essential step during the development of Burkitt lymphoma, presumably as a mechanism to escape c-myc induced apoptosis.

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Acknowledgements

We thank George Klein, Karolinska Institute, Stockholm and Gilbert Lenoir, IARC, Lyon, for providing BL cell lines and Maarten van Lohuizen, Netherlands Cancer Center, Amsterdam, Pui K Chang, Baylor College of Medicine, Houston, and Arnold J Levine, Rockefeller University, New York, for their generous gifts of antibodies. We also acknowledge Joseph Lawrence at the core sequencing facility at Cancer Center Karolinska (CCK) for skilful technical assistance and Katja Pokrovskaja, Karolinska Institute, for expertise in immunofluorescence microscopy techniques. This study was supported by the Swedish Cancer Society, the Cancer Society of Stockholm, and the Karolinska Institute.

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  1. Department of Oncology-Pathology, Karolinska Institute, Cancer Center Karolinska (CCK), Karolinska Hospital, SE-171 76, Stockholm, Sweden

    Mikael S Lindström & Klas G Wiman

  2. AB Sangtec Medical, Box 20045, SE-161 02 Bromma, Sweden

    Ulf Klangby

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Lindström, M., Klangby, U. & Wiman, K. p14ARF homozygous deletion or MDM2 overexpression in Burkitt lymphoma lines carrying wild type p53. Oncogene 20, 2171–2177 (2001). https://doi.org/10.1038/sj.onc.1204303

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