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

A. Schrader, G. Crispatzu, S. Oberbeck, P. Mayer, S. Pützer, J. Jan, E. Vasyutina, K. Warner, N. Weit, N. Pflug, T. Braun, E. I. Andersson, B. Yadav, A. Riabinska, B. Maurer, M. S. Ventura Ferreira, F. Beier, J. Altmüller, M. Lanasa, C. D. Herling, T. Haferlach, S. Stilgenbauer, G. Hopfinger, M. Peifer, T. H. Brümmendorf, P. Nürnberg, K. S. J. Elenitoba-Johnson, S. Zha, M. Hallek, R. Moriggl, H. C. Reinhardt, M.-H. Stern, S. Mustjoki, S. Newrzela, P. Frommolt and M. Herling ()
Additional contact information
A. Schrader: University of Cologne (UoC)
G. Crispatzu: University of Cologne (UoC)
S. Oberbeck: University of Cologne (UoC)
P. Mayer: University of Cologne (UoC)
S. Pützer: University of Cologne (UoC)
J. Jan: University of Cologne (UoC)
E. Vasyutina: University of Cologne (UoC)
K. Warner: University of Cologne (UoC)
N. Weit: University of Cologne (UoC)
N. Pflug: University of Cologne (UoC)
T. Braun: University of Cologne (UoC)
E. I. Andersson: University of Helsinki and Helsinki University Central Hospital (HUCH)
B. Yadav: University of Helsinki and Helsinki University Central Hospital (HUCH)
A. Riabinska: University of Cologne (UoC)
B. Maurer: Medical University of Vienna
M. S. Ventura Ferreira: RWTH Aachen University Medical School
F. Beier: RWTH Aachen University Medical School
J. Altmüller: University of Cologne (UoC)
M. Lanasa: Duke University Medical Center
C. D. Herling: University of Cologne (UoC)
T. Haferlach: MLL Munich Leukemia Laboratory
S. Stilgenbauer: University Hospital Ulm
G. Hopfinger: Medical University of Vienna
M. Peifer: UoC
T. H. Brümmendorf: RWTH Aachen University Medical School
P. Nürnberg: University of Cologne (UoC)
K. S. J. Elenitoba-Johnson: University of Pennsylvania, Perelman School of Medicine
S. Zha: Columbia University Medical Center, Columbia University
M. Hallek: University of Cologne (UoC)
R. Moriggl: Medical University of Vienna
H. C. Reinhardt: University of Cologne (UoC)
M.-H. Stern: PSL Research University
S. Mustjoki: University of Helsinki and Helsinki University Central Hospital (HUCH)
S. Newrzela: Goethe-University
P. Frommolt: UoC
M. Herling: University of Cologne (UoC)

Nature Communications, 2018, vol. 9, issue 1, 1-22

Abstract: 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 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.

Date: 2018
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DOI: 10.1038/s41467-017-02688-6

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