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

Autor:in

Schrader, Alexandra; Crispatzu, Giuliano; Oberbeck, Sebastian; Mayer, Petra; Putzer, S.; von Jan, Jana; Vasyutina, Elena; Warner, Kathrin; Weit, Nicole Yvonne; Pflug, Natali; Braun, Till; Andersson, Emma; Yadav, Bhagwan; Riabinska, Arina; Maurer, Barbara; Ferreira, Monica S. Ventura; Beier, Fabian; Altmuller, Janine; Lanasa, M.; Herling, Carmen; Haferlach, Torsten; Stilgenbauer, Stephan; Hopfinger, G.; Peifer, Martin; Bruemmendorf, Tim H.; Nuernberg, Peter; Elenitoba-Johnson, Kojo S. J.; Zha, Sang; Hallek, Michael; Moriggl, Richard; Reinhardt, Hans Christian; Stern, Marc-Henri; Mustjoki, Satu; Newrzela, Sebastian; Frommolt, Peter; Herling, Marco

Abstrakt

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.

Dokumententyp

Originalarbeit

Open Access Type

Gold

DOI

10.1038/s41467-017-02688-6

PubMed ID

MEDLINE:29449575