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.
Highlights
Research Unit Helsinki, Department of Medicine and Clinical Chemistry, University of Helsinki and Helsinki University Central Hospital (HUCH), Helsinki, 00260, Finland. 6 Institute of Animal Breeding and Genetics, University of Veterinary Medicine; Ludwig Boltzmann Institute for Cancer Research, Medical University of Vienna, Vienna, 1210, Austria. 7 Department of Hematology, Oncology, and Stem Cell Transplantation, RWTH Aachen University Medical School, Aachen, 52074, Germany. 8 Cologne Center for Genomics, UoC, Germany, Institute of Human Genetics, University of Cologne (UoC), Köln, 50937, Germany. 9 Duke University Medical Center, Durham, 27708 NC, USA
We selected treatment-naive samples from patients that were included in prospective trials or that were documented in a nationwide registry, providing thorough clinical, immunophenotypic, and cytogenetic data
Array-based gene expression profiles (GEPs) of peripheral blood (PB)-isolated tumor cells from 70 T-cell prolymphocytic leukemia (T-PLL) exhibited a differential expression (fold-change > 1.5, q < 0.05) of 2569 probes as compared to CD3+ pan T-cells isolated from 10 healthy individuals
Summary
Karyotypes of T-PLL are often complex[2,5,6,7] and include recurrent rearrangements at chromosome (chr.)[14], resulting in juxtaposition of TCL1A (T-cell leukemia/lymphoma 1A) at 14q32.1 to T-cell receptor (TCR) gene enhancers[8]. This prevents physiological post-thymic silencing of TCL1A. ATM governs the maintenance of genomic integrity by orchestrating a proper DNA damage response (DDR), including double-strand break (DSB) repair, cell cycle control, and apoptosis regulation[16,17]. We selected treatment-naive samples from patients that were included in prospective trials or that were documented in a nationwide registry, providing thorough clinical, immunophenotypic, and cytogenetic data (in part provided in Supplementary Data 1, Supplementary Fig. 1, Methods section)
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