TP 53 pathway analysis in paediatric B urkitt lymphoma reveals increased MDM 4 expression as the only TP 53 pathway abnormality detected in a subset of cases
Abstract
Summary: The TP 53 (p53) pathway can be inhibited by TP 53 mutation or deletion or by MDM 2 overexpression. Both occur in B urkitt lymphoma (BL), but many cases lack either abnormality. Expression patterns of the TP 53 inhibitor MDM 4 have not been reported in BL, and increased MDM 4 could deregulate the TP 53 pathway in cases without TP 53 or MDM 2 abnormalities. We investigated TP 53 pathway disruption in paediatric BL patient samples (n = 30) by studying MDM 4, MDM 2, and CDKN 1 A (p21) protein and m RNA expression; TP 53 mutations; TP 53 protein expression; and gene copy number abnormalities. MDM 4 protein was expressed in 30/30 tumours, and MDM 2 protein was weakly expressed in 7/30 (23%). All cases were negative for CDKN 1 A protein, and CDKN 1 A m RNA levels were decreased. TP 53 mutations were detected in 5/28 (18%) cases and confirmed by sequencing. TP 53 protein was expressed in 15/30 (50%) cases, including 7/8 with TP 53 genetic alterations. MDM 2 protein and m RNA expression levels did not correlate with lack of TP 53 genetic changes or TP 53 protein expression; however, there was an inverse relationship between detectable TP 53 protein expression and MDM 4 copy number gains and m RNA expression. The TP 53 pathway is deregulated in paediatric BL cases, and increased MDM 4 expression may be the primary mechanism in some cases.
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Mdmx is overexpressed in many human malignancies and, together with Mdm2, negatively regulates the p53 tumor suppressor.
“The oncogene Mdmx is overexpressed in many human malignancies, and together with Mdm2, negatively regulates the p53 tumor suppressor.”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [20]
MDMX is overexpressed or amplified in at least 15% of human cancers.
“MDMX, also known as MDM4, is overexpressed or amplified in at least 15% of human cancers.3,18–20”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [20]
Elevated Mdmx levels are observed in many tumors and during tumorigenesis.
“elevated Mdmx levels are observed in many tumors.3,18–22”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [20]
Cites
Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
Toledo, F., & Wahl, G. M. (2006) · Nature reviews. Cancer · doi:10.1038/nrc2012 · Cited by 1,286 · see citing works
Gaïdano, G., Ballerini, P. F., Gong, J. Z., Inghirami, G., Neri, A., Newcomb, E. W., MAGRATH, I. T., Knowles, D., & Dalla‐Favera, R. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.12.5413 · Cited by 884 · see citing works
Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis
Eischen, C. M., Weber, J. D., Roussel, M. F., Sherr, C. J., & Cleveland, J. L. (1999) · Genes & Development · doi:10.1101/gad.13.20.2658 · Cited by 819 · see citing works
Inactivation of the p53 pathway in retinoblastoma
Laurie, N. A., Donovan, S. L., Shih, C.-S., Zhang, J., Mills, N., Fuller, C., Teunisse, A., Lam, S., Ramos, Y., Mohan, A., et al. (2006) · Nature · doi:10.1038/nature05194 · Cited by 595 · see citing works
Hoffman‐Liebermann, B., & Liebermann, D. A. (2008) · Oncogene · doi:10.1038/onc.2008.312 · Cited by 485 · see citing works
Molecular Biology of Burkitt’s Lymphoma
Hecht, J. L., & Aster, J. C. (2000) · Journal of Clinical Oncology · doi:10.1200/jco.2000.18.21.3707 · Cited by 436 · see citing works
Patte, C., Auperin, A., Gerrard, M., et al. (2006) · Blood · doi:10.1182/blood-2006-07-036673 · Cited by 434 · see citing works
Cairo, M. S., Gerrard, M., Sposto, R., et al. (2006) · Blood · doi:10.1182/blood-2006-07-036665 · Cited by 365 · see citing works
Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4
Marine, J.-C., Francoz, S., Maetens, M., Wahl, G., Toledo, F., & Lozano, G. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401912 · Cited by 352 · see citing works
The p53 Tumor Suppressor Gene: From Molecular Biology to Clinical Investigation
Soussi, T. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06705.x · Cited by 330 · see citing works
Danovi, D., Meulmeester, E., Pasini, D., Migliorini, D., Capra, M., Frenk, R., de Graaf, P., Francoz, S., Gasparini, P., Gobbi, A., et al. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.13.5835-5843.2004 · Cited by 310 · see citing works
p53 is frequently mutated in Burkitt's lymphoma cell lines
Farrell, P. J., Allan, G. J., Shanahan, F., Vousden, K. H., & Crook, T. (1991) · The EMBO Journal · doi:10.1002/j.1460-2075.1991.tb07837.x · Cited by 254 · see citing works
Marine, J.-C. W., Dyer, M. A., & Jochemsen, A. G. (2007) · Journal of Cell Science · doi:10.1242/jcs.03362 · Cited by 228 · see citing works
p53 Lesions in Leukemic Transformation
Harutyunyan, A. S., Klampfl, T., Cazzola, M., & Královics, R. (2011) · New England Journal of Medicine · doi:10.1056/nejmc1012718 · Cited by 211 · see citing works
Advances in the understanding of MYC‐induced lymphomagenesis
Klapproth, K., & Wirth, T. (2010) · British Journal of Haematology · doi:10.1111/j.1365-2141.2010.08159.x · Cited by 180 · see citing works
Analysis of p53 mutations in a large series of lymphoid hematologic malignancies of childhood
Wada, M., Bartram, C., Nakamura, H., Hachiya, M., Chen, D., Borenstein, J. E., Cw, M., Ludwig, L., Hansen-Hagge, T., & Ludwig, W. (1993) · Blood · doi:10.1182/blood.v82.10.3163.3163 · Cited by 179 · see citing works
Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry?
Wade, M., & Wahl, G. M. (2009) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-08-0423 · Cited by 170 · see citing works
Aberrant expression of HDMX proteins in tumor cells correlates with wild-type p53.
Ramos, Y. F., Stad, R. K., Attema, J., Peltenburg, L. T. C., van der Eb, A. J., & Jochemsen, A. G. (2001) · PubMed · Cited by 149 · see citing works
Poirel, H.-A., Cairo, M. S., Heerema, N. A., et al. (2008) · Leukemia · doi:10.1038/leu.2008.312 · Cited by 134 · see citing works
Métay, C., Paillerets, B. B., Lefrère, I., Ronsin, M., Feunteun, J., Tursz, T., & Wiels, J. (1998) · Oncogene · doi:10.1038/sj.onc.1201702 · Cited by 123 · see citing works
The pattern of p53 mutations in Burkitt's lymphoma differs from that of solid tumors.
Bhatia, K. G., Gutiérrez, M. I., Huppi, K. E., Siwarski, D. F., & MAGRATH, I. T. (1992) · PubMed · Cited by 113 · see citing works
Rallapalli, R., Strachan, G. D., Cho, B., Mercer, W. E., & Hall, D. J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.12.8299 · Cited by 113 · see citing works
Role of genetic and epigenetic changes in Burkitt lymphoma
Lindström, M. S., & Wiman, K. G. (2002) · Seminars in Cancer Biology · doi:10.1016/s1044-579x(02)00058-5 · Cited by 111 · see citing works
Villuendas, R., Piris, M., Algara, P., Sánchez‐Beato, M., Sánchez‐Verde, L., Martinez, J., Orradre, J., García, P., López, C. G. A., & Martinez, P. (1993) · Blood · doi:10.1182/blood.v82.10.3151.3151 · Cited by 105 · see citing works
Bartel, F., Schulz, J., Böhnke, A., Blümke, K., Kappler, M., Bache, M., Schmidt, H., Würl, P., Taubert, H. W., & Hauptmann, S. (2005) · International Journal of Cancer · doi:10.1002/ijc.21206 · Cited by 93 · see citing works
Regulation of MDMX Expression by Mitogenic Signaling
Gilkes, D. M., Pan, Y., Coppola, D., Yeatman, T., Reuther, G. W., & Chen, J. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01633-07 · Cited by 82 · see citing works
Preudhomme, C., Dervite, I., Wattel, E., Vanrumbeke, M., FLACTIF, M., Laı̈, J. L., Hecquet, B., Copin, M., Nelken, B., & Gosselin, B. J. (1995) · Journal of Clinical Oncology · doi:10.1200/jco.1995.13.4.812 · Cited by 81 · see citing works
Jin, Y., Zeng, S. X., Sun, X., Lee, H., Blattner, C., Xiao, Z. J., & Lu, H. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01198-07 · Cited by 79 · see citing works
Schiffman, J. D., Lorimer, P. D., Rodic, V., et al. (2011) · British Journal of Haematology · doi:10.1111/j.1365-2141.2011.08883.x · Cited by 60 · see citing works
Self-citationInactivation of the ARF–MDM-2–p53 pathway in sporadic Burkitt's lymphoma in children
Wilda, M., Bruch, J., Harder, L., Rawer, D., Reiter, A., Borkhardt, A., & Woessmann, W. (2003) · Leukemia · doi:10.1038/sj.leu.2403254 · Cited by 59 · see citing works
Cairo, M., Krailo, M., Morse, M., et al. (2002) · Leukemia · doi:10.1038/sj.leu.2402402 · Cited by 58 · see citing works
p53 gene mutations are uncommon but p53 is commonly expressed in anaplastic large-cell lymphoma
Rassidakis, G. Z., Thomaides, A. X., Wang, S., Jiang, Y., Fourtouna, A., Lai, R., & Medeiros, L. J. (2005) · Leukemia · doi:10.1038/sj.leu.2403840 · Cited by 52 · see citing works
Han, X., Garcia‐Manero, G., McDonnell, T. J., Lozano, G., Medeiros, L. J., Xiao, L., Rosner, G. L., Nguyen, M. H., Fernandez, M., Valentin-Vega, Y. A., et al. (2006) · Modern Pathology · doi:10.1038/modpathol.3800727 · Cited by 45 · see citing works
Pediatric non-Hodgkin’s lymphoma
Gross, T. G., & Termuhlen, A. M. (2007) · Current Oncology Reports · doi:10.1007/s11912-007-0064-6 · Cited by 44 · see citing works
Correlation between mutations in p53 gene and protein expression in human lymphomas
Martínez–Delgado, B., Robledo, M., Arranz, E., Infantes, F., Echezarreta, G., Marcos, B., Sanz, C., Rivas, C., & Benitez, J. J. (1997) · American Journal of Hematology · doi:10.1002/(sici)1096-8652(199705)55:1 · Cited by 37 · see citing works
Veerakumarasivam, A., Scott, H. E., Chin, S., Warren, A. Y., Wallard, M. J., Grimmer, D., Ichimura, K., Caldas, C., Collins, V. P., Neal, D. E., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-4129 · Cited by 37 · see citing works
Bo, M. D., Secchiero, P., Degan, M., Marconi, D., Bomben, R., Pozzato, G., Gaïdano, G., Poeta, G. D., Forconi, F., Zauli, G., et al. (2010) · British Journal of Haematology · doi:10.1111/j.1365-2141.2010.08185.x · Cited by 26 · see citing works
Mdm2 Regulates p53 Independently of p19ARF in Homeostatic Tissues
O’Leary, K. A., Mendrysa, S. M., Vaccaro, A. M., & Perry, M. E. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.24.1.186-191.2004 · Cited by 25 · see citing works
Liang, M., Han, X., Vadhan‐Raj, S., Nguyen, M. H., Zhang, Y. H., Fernandez, M., Drakos, E., Konoplev, S. N., Yin, C. C., Miranda, R. N., et al. (2010) · Modern Pathology · doi:10.1038/modpathol.2009.170 · Cited by 22 · see citing works
p53 protein expression in non‐Hodgkin's lymphomas is infrequently related to p53 gene mutations
Oka, T., Sarker, A. B., Teramoto, N., et al. (1998) · Pathology International · doi:10.1111/j.1440-1827.1998.tb03822.x · Cited by 13 · see citing works
p53 protein expression does not correlate with EBV status in childhood B non‐hodgkin lymphomas
Klumb, C. E., Hassan, R., Zalcberg, I. R., et al. (2004) · Pediatric Blood & Cancer · doi:10.1002/pbc.20069 · Cited by 11 · see citing works
The RB (pRb2/p16) and p53 (p14/p53/p21) Tumor-suppressor Pathways in Endemic Burkitt Lymphoma
Kalungi, S., Wabinga, H., & Bostad, L. H. (2010) · Journal of Pediatric Hematology/Oncology · doi:10.1097/mph.0b013e3181edf543 · Cited by 6 · see citing works
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The Mdm network and its regulation of p53 activities: a rheostat of cancer risk
Eischen, C. M., & Lozano, G. (2014) · Human Mutation · doi:10.1002/humu.22524 · Cited by 79 · see citing works
Mdmx promotes genomic instability independent of p53 and Mdm2
Carrillo, A. M., Bouska, A., Arrate, M. P., & Eischen, C. M. (2015) · Oncogene · doi:10.1038/onc.2014.27 · Cited by 69 · see citing works
- Authors
- Leventaki, V., Rodic, V., Tripp, S. R., Bayerl, M. G., Perkins, S. L., Barnette, P., Schiffman, J. D., & Miles, R. R.
- Affiliations
- University of Utah (US)
- ARUP Institute for Clinical and Experimental Pathology (US)
- Pennsylvania State University (US)
- Corresponding author
- Miles, Rodney R.
- Venue
- British Journal of Haematology
- Publisher
- Wiley
- Published
- 2012-07-27
- Volume
- 158
- Issue
- 6
- Pages
- 763-771
- ISSN
- 0007-1048 (ISSN-L)
- 1365-2141
- OpenAlex
- W2054137427
- Cited by
- 26
- References
- 42
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 3 · 2015: 2 · 2014: 6
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- British Journal of Haematology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Penn State College of Medicine
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Keywords
- p53 pathway, MDM4, MDM2, p21, TP53 mutation
- MeSH terms
- Burkitt Lymphoma, DNA, Neoplasm, Humans, Neoplasm Proteins, Nuclear Proteins, Proto-Oncogene Proteins, RNA, Messenger, RNA, Neoplasm, Signal Transduction, Gene Expression Regulation, Neoplastic, Genes, p53, Tumor Suppressor Protein p53, Cell Cycle Proteins, Cyclin-Dependent Kinase Inhibitor p21, Proto-Oncogene Proteins c-mdm2
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