Details

Autor(en) / Beteiligte

• 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.
• Ventura Ferreira, M. S.
• Beier, F.
• Altmüller, 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.

Titel

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

Ist Teil von

• Nature communications, 2018-02, Vol.9 (1), p.697-22, Article 697

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.