p53 allele deletion and protein accumulation occurs in the absence of p53 gene mutation in T‐prolymphocytic leukaemia and Sezary syndrome

Abstract

Summary. In a series of 24 patients with chronic T-lymphoid disorders [13 T-prolymphocytic leukaemia (T-PLL) and 11Sezary syndrome] we have studied (i) chromosome 17p abnormalities and p53 allele deletion by fluorescence in situ hybridization; (ii) mutation in the exons of the p53 gene by direct DNA sequencing; and (iii) p53 protein expression by immunocytochemistry and, in some cases, also by flow cytometry with DO-1, a monoclonal antibody to the p53 protein. The study revealed p53 deletion and accumulation of p53 protein in the absence of mutation in the exons that included the hot-spots and differs from that described in B-prolymphocytic leukaemia. Seven T-PLL and five Sezary syndrome patients had p53 overexpression, and five T-PLL and nine Sezary syndrome patients showed p53 deletion. Although the majority of cases with p53 accumulation had p53 deletion, the proportion of cells with the deletion did not correlate with the proportion of cells positive for p53 expression. Two cases of T-PLL showed strong p53 expression in the absence of p53 deletion, and one case of Sezary syndrome with p53 deletion in 97% of cells did not express p53. These findings suggest that a non-mutational mechanism exists for the accumulation of p53 protein in these T-cell disorders. The oncogenic effect of the accumulating wild-type protein has been reported in other malignancies. Whether haploidy resulting from p53 deletion contributes to this mechanism has yet to be determined. Alternatively, the frequent loss of the p53 gene could be associated with the deletion of an adjacent gene, which could be involved in the pathogenesis of these diseases.

Molecular cytogenetic analysis of cutaneous T-cell lymphomas: identification of common genetic alterations in Sezary syndrome and mycosis fungoides

“…Previous allelotyping studies from our group have also reported LOH at 17p in 10% of MF cases using microsatellite markers flanking the p53 gene 18 . Deletion of 17p has been commonly found in various tumours including leukaemia and lymphoma, 29–31 and our previous studies have also shown high rates of p53 gene mutations in advanced stages of MF 13 . These results suggest that inactivation of genes on 17p, including p53 , may be related to disease progression in CTCL.…”

In utero Exposure of Mice to Dibenzo[a,l]Pyrene Produces Lymphoma in the Offspring: Role of the Aryl Hydrocarbon Receptor

“…TP53 mutations are frequently observed in human lung cancers (53) whereas the role of TP53 mutations in T-cell lymphomas is not entirely clear, perhaps owing to the number of different cell lineages from which the lymphomas arise. Alterations in p53 are frequently found in human leukemia-lymphoma cell lines (54) and certain T-cell lymphomas in humans have a high incidence of TP53 mutations (55) whereas others display p53 dysregulation without mutation (56). In this study, 3 of 14 lung adenomas from offspring born to mothers exposed to DBP during pregnancy exhibited Ki-ras mutations, a frequency markedly lower than seen following transplacental exposure to other PAHs in other mouse strains (47).…”

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…However, overexpression and accumulation of wild-type TP53 is common in T-PLL [110]. In ALK + ALCL, which is driven by NPM-ALK, the fusion kinase can efficiently block wild-type TP53 function [111].…”