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  • The tumour suppressor p53 is frequently nonfunctional in Sézary syndrome.

The tumour suppressor p53 is frequently nonfunctional in Sézary syndrome.

The British journal of dermatology (2012-03-06)
B Lamprecht, S Kreher, M Möbs, W Sterry, B Dörken, M Janz, C Assaf, S Mathas
ABSTRACT

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. 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. 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. We identified various TP53 mutations and an impaired p53 signalling in the vast majority of the investigated cell lines and primary SS cells. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-74, ascites fluid
Sigma-Aldrich
Nutlin-3, InSolution, ≥98%, Racemic, potent and selective MDM2 antagonist
Sigma-Aldrich
Anti-p53 (Ab-2) (Pantropic) Mouse mAb (PAb1801), liquid, clone PAb1801, Calbiochem®
Sigma-Aldrich
Anti-α-Tubulin antibody, Mouse monoclonal, clone DM1A, purified from hybridoma cell culture