TP53 pathway analysis in paediatric Burkitt lymphoma reveals increased MDM4 expression as the only TP53 pathway abnormality detected in a subset of cases

• Published in: British journal of haematology 2012-09, Vol.158 (6), p.763-771
• Main Authors: Leventaki, Vasiliki, Rodic, Vladimir, Tripp, Sheryl R., Bayerl, Michael G., Perkins, Sherrie L., Barnette, Phillip, Schiffman, Joshua D., Miles, Rodney R.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Burkitt lymphoma; Burkitt Lymphoma - genetics; Burkitt Lymphoma - metabolism; Burkitt Lymphoma - pathology; Burkitt's lymphoma; copy number; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p21 - genetics; DNA, Neoplasm - genetics; Gene deletion; Gene expression; Gene Expression Regulation, Neoplastic; Genes, p53; Hematologic and hematopoietic diseases; Humans; Infectious diseases; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; MDM2; MDM2 protein; MDM4; Medical sciences; Mutation; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Nuclear Proteins; p53 protein; paediatric; Pediatrics; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2 - biosynthesis; Proto-Oncogene Proteins c-mdm2 - genetics; RNA, Messenger - genetics; RNA, Neoplasm - genetics; Signal Transduction; TP53; Tumor Suppressor Protein p53 - biosynthesis; Tumor Suppressor Protein p53 - physiology; Tumors; Viral diseases
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2012.09243.x

Summary The TP53 (p53) pathway can be inhibited by TP53 mutation or deletion or by MDM2 overexpression. Both occur in Burkitt lymphoma (BL), but many cases lack either abnormality. Expression patterns of the TP53 inhibitor MDM4 have not been reported in BL, and increased MDM4 could deregulate the TP53 pathway in cases without TP53 or MDM2 abnormalities. We investigated TP53 pathway disruption in paediatric BL patient samples (n = 30) by studying MDM4, MDM2, and CDKN1A (p21) protein and mRNA expression; TP53 mutations; TP53 protein expression; and gene copy number abnormalities. MDM4 protein was expressed in 30/30 tumours, and MDM2 protein was weakly expressed in 7/30 (23%). All cases were negative for CDKN1A protein, and CDKN1A mRNA levels were decreased. TP53 mutations were detected in 5/28 (18%) cases and confirmed by sequencing. TP53 protein was expressed in 15/30 (50%) cases, including 7/8 with TP53 genetic alterations. MDM2 protein and mRNA expression levels did not correlate with lack of TP53 genetic changes or TP53 protein expression; however, there was an inverse relationship between detectable TP53 protein expression and MDM4 copy number gains and mRNA expression. The TP53 pathway is deregulated in paediatric BL cases, and increased MDM4 expression may be the primary mechanism in some cases.