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

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 a ect 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. Oncogene (2001) 20, 2170 ± 2177.

Activation of p53 by MDM2 antagonists has differential apoptotic effects on Epstein–Barr virus (EBV)-positive and EBV-negative Burkitt's lymphoma cells

“…8,22 Finally, another study has shown that p14 ARF , which regulates the function of p53, is frequently altered in BL cell lines carrying wt p53. 23 All these data clearly demonstrate that disruption of the p53 pathway contributes to BL development. 24,25 They also suggest that the restoration of wt p53 function in BL cells may be an efficient treatment strategy, at least in patients with cancers resistant to standard chemotherapy treatments.…”

Myc pathways provoking cell suicide and cancer

“…Thus, these apoptotic pathways are bypassed during tumorigenesis in an independent fashion. Further, these events are relevant to the human condition, as BL have a similar frequency in hits in the ARF-Mdm2-p53 pathway (Lindstrom et al, 2001).…”

Intensive expression of Bmi-1 is a new independent predictor of poor outcome in patients with ovarian carcinoma

“…It has been discovered that Bmi-1 participates in cell cycle regulation by acting as a stable transcriptional repressor of the Ink4a locus, which encodes the tumor suppressor proteins p16Ink4a and p19Arf (mouse homologue of human p14ARF). Inactivation of the p16Ink4a-pRb pathway and p14ARF-MDM2-p53 pathway by Bmi-1 deregulation has been clearly implicated in lymphomagenesis [9,10] and oncogenesis in nonsmall-cell lung cancer of human [11]. This suggested that the Bmi-1 gene plays an important role in cell proliferation and tumor progression.…”