The tumour suppressor p53 is frequently nonfunctional in Sezary syndrome
Autor/innen
- B. Lamprecht
- S. Kreher
- M. Moebs
- W. Sterry
- B. Doerken
- M. Janz
- C. Assaf
- S. Mathas
Journal
- British Journal of Dermatology
Quellenangabe
- Br J Dermatol 167 (2): 240-246
Zusammenfassung
Background: Primary cutaneous T cell lymphomas (CTCLs) are a heterogenous group with Sezary syndrome (SS) as one of its most aggressive variants. Recently, we identified a loss of E2A as a recurrent event in SS, which enhanced proliferation via up-regulation 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. Objectives: We investigated functionality of p53 signaling by pharmacological treatment with the MDM2 antagonist nutlin-3, which might result in p53 activation. Furthemore, we analyzed the TP53 mutation status in CTCL cell lines and highly purified tumor cells from SS patients 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 / propiumiodide 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 signaling in the vast majority of the investigated cell lines and primary SS cells. Conclusion: In accordance with the importance of MYC deregulation in SS, p53 signaling is frequently non-functional 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.