Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL

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.; Herling, M.

Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL

Tools

Preview	PDF (Original Article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader 6MB
	Other (Supplementary data) 35MB

Item Type:	Article
Title:	Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL
Creators:	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. ORCID: https://orcid.org/0000-0002-3986-9892, Yadav, B., Riabinska, A., Maurer, B., Ventura Ferreira, M.S., Beier, F., Altmüller, J. ORCID: https://orcid.org/0000-0003-4372-1521, Lanasa, M., Herling, C.D., Haferlach, T., Stilgenbauer, S., Hopfinger, G., Peifer, M. ORCID: https://orcid.org/0000-0002-5243-5503, Brümmendorf, T.H., Nürnberg, P., Elenitoba-Johnson, K.S.J., Zha, S., Hallek, M., Moriggl, R. ORCID: https://orcid.org/0000-0003-0918-9463, Reinhardt, H.C., Stern, M.H. ORCID: https://orcid.org/0000-0002-8100-2272, 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

Repository Staff Only: item control page

Download Statistics

Downloads

Downloads per month over past year