| Autor: |
Weeks RJ; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. rob.weeks@otago.ac.nz., Ludgate JL; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand., Le Mée G; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand., Khanal R; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand., Mehta S; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand., Williams G; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand., Slatter TL; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand., Braithwaite AW; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand., Morison IM; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. |
| Abstrakt: |
The tumour suppressor gene, TES, is frequently methylated in many human tumours. Previously, we demonstrated that TES promoter methylation and transcriptional silencing was the most common molecular abnormality detected in childhood acute lymphoblastic leukaemia (ALL). Trp53-mutant mouse models predominantly develop B- and T-cell lymphomas, which are widely considered equivalent to childhood T and B ALL. In this study, we examined expression of Tes transcript and Testin protein in spontaneous tumours obtained from three Trp53-mutant mouse models. Using immunohistochemistry, we report that 47% of lymphomas lacked Testin protein compared to only 7% of non-lymphoid tumours. Further examination of the lymphomas from Trp53-null and Trp53-mΔpro homozygous mutant mice revealed that 63% and 69% respectively of the isolated lymphomas were Testin negative, which is similar to reported rates in childhood T-ALL. Surprisingly, lymphomas from Trp53-Δ122 mice were frequently Testin positive (> 60%), suggesting that the presence of the Trp53-Δ122 protein appeared to mitigate the requirement for Tes silencing in lymphomagenesis. Quantitative RT-PCR results confirmed that this lack of Testin protein was due to Tes transcriptional silencing, although bisulfite sequencing demonstrated that this was not due to promoter methylation. These results are consistent with the Testin protein having lymphoid tumour suppressor activity in both mice and humans. |
