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| Item Type: | Article |
|---|---|
| Title: | Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL |
| Creators Name: | Schrader, A., Crispatzu, G., Oberbeck, S., Mayer, P., Pützer, S., von Jan, J., Vasyutina, E., Warner, K., Weit, N., Pflug, N., Braun, T., Andersson, E.I., Yadav, B., Riabinska, A., Maurer, B., Ventura Ferreira, M.S., Beier, F., Altmüller, J., Lanasa, M., Herling, C.D., Haferlach, T., Stilgenbauer, S., Hopfinger, G., Peifer, M., Brümmendorf, T.H., Nürnberg, P., Elenitoba-Johnson, K.S.J., Zha, S., Hallek, M., Moriggl, R., Reinhardt, H.C., Stern, M.H., Mustjoki, S., Newrzela, S., Frommolt, P. and Herling, M. |
| Abstract: | T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution. |
| Keywords: | Ataxia Telangiectasia Mutated Proteins, Tumor Cell Line, DNA Damage, Genetic Epigenesis, Gene Expression Profiling, HEK293 Cells, Kaplan-Meier Estimate, T-Cell Prolymphocytic Leukemia, Transgenic Mice, Mutation, Proto-Oncogene Proteins, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 9 |
| Number: | 1 |
| Page Range: | 697 |
| Date: | 15 February 2018 |
| Official Publication: | https://doi.org/10.1038/s41467-017-02688-6 |
| PubMed: | View item in PubMed |
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