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

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http://hdl.handle.net/10138/234167

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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 , Ferreira , M S V , Beier , F , Altmueller , 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 2018 , ' Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL ' , Nature Communications , vol. 9 , 697 . https://doi.org/10.1038/s41467-017-02688-6

Title: Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL
Author: 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.; Ferreira, M. S. Ventura; Beier, F.; Altmueller, 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.
Contributor: University of Helsinki, Faculty of Medicine
University of Helsinki, Medicum
University of Helsinki, Medicum
Date: 2018-02-15
Language: eng
Number of pages: 22
Belongs to series: Nature Communications
ISSN: 2041-1723
URI: http://hdl.handle.net/10138/234167
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.
Subject: CELL PROLYMPHOCYTIC LEUKEMIA
CHRONIC LYMPHOCYTIC-LEUKEMIA
ACUTE MYELOID-LEUKEMIA
DOUBLE-STRAND BREAK
ATM KINASE-ACTIVITY
ATAXIA-TELANGIECTASIA
DNA-DAMAGE
GENOMIC INSTABILITY
EMBRYONIC LETHALITY
TELOMERASE ACTIVITY
3111 Biomedicine
3122 Cancers
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