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The tumour suppressor p53 is frequently nonfunctional in Sezary syndrome

Item Type:Article
Title:The tumour suppressor p53 is frequently nonfunctional in Sezary syndrome
Creators Name:Lamprecht, B. and Kreher, S. and Moebs, M. and Sterry, W. and Doerken, B. and Janz, M. and Assaf, C. and Mathas, S.
Abstract: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.
Keywords:Apoptosis, Cell Proliferation, DNA Sequence Analysis, Genes, p53, Imidazoles, Immunoblotting, Loss of Heterozygosity, Mutation, Piperazines, Proto-Oncogene Proteins c-mdm2, Sezary Syndrome, Signal Transduction, Skin Neoplasms, Tumor Cell Line, Tumor Suppressor Protein p53
Source:British Journal of Dermatology
ISSN:0007-0963
Publisher:Wiley-Blackwell (U.K.)
Volume:167
Number:2
Page Range:240-246
Date:August 2012
Official Publication:https://doi.org/10.1111/j.1365-2133.2012.10918.x
PubMed:View item in PubMed

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