Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL
| Autor: | Torsten Haferlach, Nicole Weit, Elena Vasyutina, Sebastian Newrzela, Giuliano Crispatzu, Bhagwan Yadav, Georg Hopfinger, Peter Nürnberg, Marc-Henri Stern, Till Braun, Sebastian Oberbeck, Hans Christian Reinhardt, Richard Moriggl, T H Brümmendorf, S. Pützer, Kathrin Warner, Petra Mayer, Satu Mustjoki, Fabian Beier, J. von Jan, Peter Frommolt, Kojo S.J. Elenitoba-Johnson, Shan Zha, Stephan Stilgenbauer, Natali Pflug, Martin Peifer, Alexandra Schrader, Carmen D. Herling, Barry J. Maurer, Mark C. Lanasa, Emma I. Andersson, Marco Herling, Arina Riabinska, Michael Hallek, Janine Altmüller, M. S. Ventura Ferreira |
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| Přispěvatelé: | Faculty of Medicine, Medicum, Department of Clinical Chemistry and Hematology, Clinicum, Hematologian yksikkö, University of Helsinki, Department of Oncology, HUS Comprehensive Cancer Center |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Genome instability General Physics and Astronomy Ataxia Telangiectasia Mutated Proteins Kaplan-Meier Estimate Epigenesis Genetic lcsh:Science Multidisciplinary CELL PROLYMPHOCYTIC LEUKEMIA ATM KINASE-ACTIVITY Middle Aged EMBRYONIC LETHALITY Histone Female Technology Platforms Adult DNA damage Science 3122 Cancers Mice Transgenic ACUTE MYELOID-LEUKEMIA Biology TELOMERASE ACTIVITY Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences DOUBLE-STRAND BREAK Cell Line Tumor Proto-Oncogene Proteins medicine Animals Humans Epigenetics ATAXIA-TELANGIECTASIA Aged CHRONIC LYMPHOCYTIC-LEUKEMIA Gene Expression Profiling General Chemistry medicine.disease Telomere Gene expression profiling HEK293 Cells 030104 developmental biology DNA-DAMAGE Leukemia Prolymphocytic T-Cell Mutation Ataxia-telangiectasia biology.protein Cancer research lcsh:Q 3111 Biomedicine DNA Damage GENOMIC INSTABILITY |
| Zdroj: | Nature Communications 9, 697 (2018). doi:10.1038/s41467-017-02688-6 Nature Communications Nature Communications, Vol 9, Iss 1, Pp 1-22 (2018) |
| Popis: | 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. T-cell prolymphocytic leukemia (T-PLL) is a rare malignancy with a poor prognosis. Here, the authors investigate the genomic landscape, gene expression profiles and functional mechanisms in 111 patients, highlighting TCL1 overexpression and ATM aberrations as core lesions which co-operate to impair DNA damage processing. |
| Databáze: | OpenAIRE |
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