MDM2 phenotypic and genotypic profiling, respective to TP53 genetic status, in diffuse large B-cell lymphoma patients treated with rituximab-CHOP immunochemotherapy: a report from the International DLBCL Rituximab-CHOP Consortium Program.

MDM2 is a key negative regulator of the tumor suppressor p53, however, the prognostic significance of MDM2 overexpression in diffuse large B-cell lymphoma (DLBCL) has not been defined convincingly. In a p53 genetically-defined large cohort of de novo DLBCL patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, we assessed MDM2 and p53 expression by immunohistochemistry (n = 478), MDM2 gene amplification by fluorescence in situ hybridization (n = 364), and a single nucleotide polymorphism in the MDM2 promoter, SNP309, by SNP genotyping assay (n = 108). Our results show that MDM2 overexpression, unlike p53 overexpression, is not a significant prognostic factor in overall DLBCL. Both MDM2 and p53 overexpression do not predict for an adverse clinical outcome in patients with wild-type p53 but predicts for significantly poorer survival in patients with mutated p53. Variable p53 activities may ultimately determine the survival differences, as suggested by the gene expression profiling analysis. MDM2 amplification was observed in 3 of 364 (0.8%) patients with high MDM2 expression. The presence of SNP309 did not correlate with MDM2 expression and survival. This study indicates that evaluation of MDM2 and p53 expression correlating with TP53 genetic status is essential to assess their prognostic significance and is important for designing therapeutic strategies that target the MDM2-p53 interaction.

[1]  W. Choi,et al.  Mutational Profile and Prognostic Significance of TP53 in Diffuse Large B-cell Lymphoma Patients Treated with Rituximab-CHOP: A Report From an International DLBCL Rituximab-CHOP Consortium Program Study , 2013 .

[2]  W. Choi,et al.  Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL Rituximab-CHOP Consortium Program Study. , 2012, Blood.

[3]  K. Dybkær,et al.  Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study , 2012, Leukemia.

[4]  Carol Prives,et al.  Mutant p53: one name, many proteins. , 2012, Genes & development.

[5]  Timothy C Greiner,et al.  Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies. , 2012, Blood.

[6]  In Hye Lee,et al.  Atg7 Modulates p53 Activity to Regulate Cell Cycle and Survival During Metabolic Stress , 2012, Science.

[7]  S. Deb,et al.  Gain-of-function mutant p53 upregulates CXC chemokines and enhances cell migration. , 2012, Carcinogenesis.

[8]  A. El‐Naggar,et al.  Multiple stress signals activate mutant p53 in vivo. , 2011, Cancer research.

[9]  T. Hupp,et al.  p21WAF1 is component of a positive feedback loop that maintains the p53 transcriptional program , 2011, Cell cycle.

[10]  Sandeep Krishna,et al.  Stress-specific response of the p53-Mdm2 feedback loop , 2010, BMC Systems Biology.

[11]  M. Kaufman,et al.  From structure to dynamics: frequency tuning in the p53-Mdm2 network. II Differential and stochastic approaches. , 2010, Journal of theoretical biology.

[12]  Kyoohyoung Rho,et al.  A theoretical model for p53 dynamics: Identifying optimal therapeutic strategy for its activation and stabilization , 2009, Cell cycle.

[13]  H. Leonhardt,et al.  MBD4 and MLH1 are required for apoptotic induction in xDNMT1-depleted embryos , 2009, Development.

[14]  Galina Selivanova,et al.  MDM2-dependent downregulation of p21 and hnRNP K provides a switch between apoptosis and growth arrest induced by pharmacologically activated p53. , 2009, Cancer cell.

[15]  V. Rusch,et al.  SCCRO (DCUN1D1) Induces Extracellular Matrix Invasion by Activating Matrix Metalloproteinase 2 , 2008, Clinical Cancer Research.

[16]  Tomasz Lipniacki,et al.  Oscillations and bistability in the stochastic model of p53 regulation. , 2008, Journal of theoretical biology.

[17]  R. Fåhraeus,et al.  p53 mRNA controls p53 activity by managing Mdm2 functions , 2008, Nature Cell Biology.

[18]  Carole J. Proctor,et al.  Explaining oscillations and variability in the p53-Mdm2 system , 2008, BMC Systems Biology.

[19]  Guillermina Lozano,et al.  Mdm2 and Mdm4 Loss Regulates Distinct p53 Activities , 2008, Molecular Cancer Research.

[20]  T. Iwakuma,et al.  The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss. , 2008, Genes & development.

[21]  K. Roemer,et al.  MDM2 gene SNP309 T/G and p53 gene SNP72 G/C do not influence diffuse large B-cell non-Hodgkin lymphoma onset or survival in central European Caucasians , 2008, BMC Cancer.

[22]  T. Greiner,et al.  Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells , 2008, Oncogene.

[23]  K. Vousden,et al.  Ubiquitination and Degradation of Mutant p53 , 2007, Molecular and Cellular Biology.

[24]  B. Cheson.  The International Harmonization Project for response criteria in lymphoma clinical trials. , 2007, Hematology/oncology clinics of North America.

[25]  M. Olivier,et al.  Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database , 2007, Human mutation.

[26]  A. Rosenwald,et al.  Increased MDM2 expression is associated with inferior survival in mantle-cell lymphoma, but not related to the MDM2 SNP309. , 2007, Haematologica.

[27]  Gustavo Stolovitzky,et al.  A single nucleotide polymorphism in the MDM2 gene disrupts the oscillation of p53 and MDM2 levels in cells. , 2007, Cancer research.

[28]  Alnawaz Rehemtulla,et al.  Real-time evaluation of p53 oscillatory behavior in vivo using bioluminescent imaging. , 2006, Cancer research.

[29]  R. Milo,et al.  Oscillations and variability in the p53 system , 2006, Molecular systems biology.

[30]  A. Levine,et al.  p53-Mdm2 loop controlled by a balance of its feedback strength and effective dampening using ATM and delayed feedback. , 2005, Systems biology.

[31]  John Jeremy Rice,et al.  A plausible model for the digital response of p53 to DNA damage. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[32]  A. Fourtouna,et al.  p53 gene mutations are uncommon but p53 is commonly expressed in anaplastic large-cell lymphoma , 2005, Leukemia.

[33]  Andrea Ciliberto,et al.  Steady States and Oscillations in the p53/Mdm2 Network , 2005, Cell cycle.

[34]  A. Levine,et al.  A Single Nucleotide Polymorphism in the MDM2 Promoter Attenuates the p53 Tumor Suppressor Pathway and Accelerates Tumor Formation in Humans , 2004, Cell.

[35]  C. Cordon-Cardo,et al.  MDM2 and prognosis. , 2004, Molecular cancer research : MCR.

[36]  Guillermina Lozano,et al.  MDM2, an introduction. , 2003, Molecular cancer research : MCR.

[37]  S. Deb.  Cell cycle regulatory functions of the human oncoprotein MDM2. , 2003, Molecular cancer research : MCR.

[38]  N. Monk.  Oscillatory Expression of Hes1, p53, and NF-κB Driven by Transcriptional Time Delays , 2003, Current Biology.

[39]  O. Nielsen,et al.  Frequent alteration of MDM2 and p53 in the molecular progression of recurring non-Hodgkin's lymphoma. , 2002, Histopathology.

[40]  M. Roussel,et al.  The RING domain of Mdm2 can inhibit cell proliferation. , 2002, Cancer research.

[41]  C. Maki,et al.  MDM2 Can Promote the Ubiquitination, Nuclear Export, and Degradation of p53 in the Absence of Direct Binding* , 2001, The Journal of Biological Chemistry.

[42]  Jiandong Chen,et al.  Stabilization of the MDM2 Oncoprotein by Mutant p53* , 2001, The Journal of Biological Chemistry.

[43]  U Alon,et al.  Generation of oscillations by the p53-Mdm2 feedback loop: a theoretical and experimental study. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[44]  O. Nielsen,et al.  Oncoprotein MDM2 overexpression is associated with poor prognosis in distinct non-Hodgkin's lymphoma entities. , 1999, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[45]  T. McDonnell,et al.  Loss of one but not two mdm2 null alleles alters the tumour spectrum in p53 null mice , 1999, The Journal of pathology.

[46]  L. Donehower,et al.  Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[47]  T. Tursz,et al.  Overexpression of MDM2, due to enhanced translation, results in inactivation of wild-type p53 in Burkitt's lymphoma cells , 1998, Oncogene.

[48]  D. Spandidos,et al.  A MOLECULAR AND IMMUNOHISTOCHEMICAL STUDY OF THE MDM2 PROTEIN ISOFORMS AND p53 GENE PRODUCT IN BRONCHOGENIC CARCINOMA , 1996, The Journal of pathology.

[49]  K. Dybkær,et al.  Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study , 2014, Leukemia.

[50]  J. Marine,et al.  Mdm2-mediated ubiquitylation: p53 and beyond , 2010, Cell Death and Differentiation.

[51]  D. Catovsky,et al.  p53 and mdm2 in mantle cell lymphoma in leukemic phase. , 2002, Haematologica.

[52]  Uri Alon,et al.  Dynamics of the p53-Mdm2 feedback loop in individual cells , 2004, Nature Genetics.