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: 2041-1723

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.

Full text


Alkylating deacetylase inhibitor tinostamustine in T-PLL

March 11, 2020

New letter evaluating the effects of EDO-S101/tinostamustine published in Leukemia.

Advances and Perspectives in the Treatment of T-PLL

Advances and Perspectives in the Treatment of T-PLL

February 25, 2020

New review on current and future strategies in treating T-PLL published in Current Hematologic Malignancy Reports

JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL

November 21, 2019

New meta-analysis on JAK/STAT genomic alterations in T-PLL published in Cancers.

We congratulate Dr. Sebastian Oberbeck on his PhD defence!

We congratulate Dr. Sebastian Oberbeck on his PhD defence!

October 30, 2019

On October 30th, Sebastian Oberbeck successfully defended his PhD. Congratulations!