p14ARF homozygous deletion or MDM2 overexpression in Burkitt lymphoma lines carrying wild type p53.
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.
Lindström
M S
MS
Karolinska Institute, Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Hospital, SE-171 76 Stockholm, Sweden.
Klangby
U
U
Wiman
K G
KG
D002051:Burkitt Lymphoma / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16 / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D017354:Point Mutation; D063150:Polycomb Repressive Complex 1; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF
C069077:BMI1 protein, human; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D025803:Tumor Suppressor Protein p14ARF; C497206:MDM2 protein, human; D063150:Polycomb Repressive Complex 1; D051736:Proto-Oncogene Proteins c-mdm2