title: The tumour suppressor p53 is frequently nonfunctional in Sézary syndrome.
abstract: BACKGROUND
  Primary cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group with Sézary syndrome (SS) as one of the most aggressive variants. Recently, we identified a loss of E2A as a recurrent event in SS, which enhanced proliferation via upregulation of the proto-oncogene MYC. MYC-induced transformation usually requires deleterious alterations of key apoptotic genes including p53; however, p53 functionality and mutation status in SS are unclear.
  
  
  OBJECTIVE
  We investigated functionality of p53 signalling by pharmacological treatment with the MDM2 antagonist nutlin-3, which might result in p53 activation. Furthermore, we analysed the TP53 mutation status in CTCL cell lines and highly purified tumour cells from patients with SS by mRNA and DNA sequencing.
  
  
  METHODS
  We analysed the apoptosis induction due to nutlin-3 treatment in various SS cell lines and primary patient samples by annexin V/propidium iodide staining. Induction of p53 target genes was analysed by immunoblotting, and TP53 was sequenced at the mRNA and DNA level.
  
  
  RESULTS
  We identified various TP53 mutations and an impaired p53 signalling in the vast majority of the investigated cell lines and primary SS cells.
  
  
  CONCLUSIONS
  In accordance with the importance of MYC deregulation in SS, p53 signalling is frequently nonfunctional in SS. However, although most likely ineffective as exclusive treatment in SS, it remains possible that pharmacological p53 activation could be beneficial in combination with other approaches including classical chemotherapeutics.
authors.affiliation: Department of Haematology, Oncology and Tumour Immunology, Charité- Universitätsmedizin Berlin, 13125 Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Lamprecht
authors.forename: S
authors.initials: S
authors.lastname: Kreher
authors.forename: M
authors.initials: M
authors.lastname: Möbs
authors.forename: W
authors.initials: W
authors.lastname: Sterry
authors.forename: B
authors.initials: B
authors.lastname: Dörken
authors.forename: M
authors.initials: M
authors.lastname: Janz
authors.forename: C
authors.initials: C
authors.lastname: Assaf
authors.forename: S
authors.initials: S
authors.lastname: Mathas
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D019656:Loss of Heterozygosity; D009154:Mutation / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D012751:Sezary Syndrome / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
chemical_list: D007093:Imidazoles; C000715470:MAS1 protein, human; D010879:Piperazines; D000090063:Proto-Oncogene Mas; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2