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The tumour suppressor p53 is frequently nonfunctional in Sézary syndrome
Author(s) -
Lamprecht B.,
Kreher S.,
Möbs M.,
Sterry W.,
Dörken B.,
Janz M.,
Assaf C.,
Mathas S.
Publication year - 2012
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/j.1365-2133.2012.10918.x
Subject(s) - cancer research , mdm2 , apoptosis , propidium iodide , downregulation and upregulation , oncogene , biology , cell culture , mutation , suppressor , cell cycle , gene , medicine , programmed cell death , genetics
Summary 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. Objectives 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.