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

作者：Schrader A; Crispatzu G; Oberbeck S; Mayer P; Putzer 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; Bruemmendorf T H; Nuernberg P; Elenitoba Johnson K S J; Zha S; Hallek M; Moriggl R; Reinhardt H C; Stern M H; Mustjoki S; Newrzela S

来源：Nature Communications, 2018, 9(1): 697.

DOI：10.1038/s41467-017-02688-6

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.

• 出版日期2018-2-15