Laboratory of Lymphocyte Signaling and Oncoproteome

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, EI Yadav, B Riabinska, A Maurer, B Ventura Ferreira, MS Beier, F Altmüller, J Lanasa, M Herling, CD Haferlach, T Stilgenbauer, S Hopfinger, G Peifer, M Brümmendorf, TH Nürnberg, P Elenitoba-Johnson, KSJ Zha, S Hallek, M Moriggl, R Reinhardt, HC Stern, MH Mustjoki, S Newrzela, S Frommolt, P Herling, M
Nature Communications 9, 1February, 2018doi: 10.1038/s41467-017-02688-6ISSN: 2041-1723https://www.nature.com/articles/s41467-017-02688-6/

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 TCL1overexpression 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.

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