|
| Status |
Public on Nov 30, 2017 |
| Title |
The molecular basis of T-PLL is an actionable perturbation of TCL1/ATM- and epigenetically instructed damage responses [human SNP array] |
| Organism |
Homo sapiens |
| Experiment type |
Genome variation profiling by SNP array
|
| Summary |
T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. To address its incomplete molecular concept, 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 identified 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 towards 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.
|
| |
|
| Overall design |
Purified T-cells from 98 T-PLL patients (Supplementary Data1 for additional information) were analyzed using various high-throughput profiling platforms (overlap indicated): Affymetrix SNP 6.0 arrays (n=83 cases) for analysis of somatic copy-number alterations (sCNAs). For sCNA profiling patient-derived germline control DNA from 13 t/g pairs of the 83 cases) were used as a pooled reference alone or in combination with publically available HapMap data sets (http://hapmap.ncbi.nlm. nih.gov/).
|
| |
|
| Citation(s) |
29449575 |
| Submission date |
Nov 29, 2017 |
| Last update date |
Nov 27, 2018 |
| Contact name |
Giuliano Crispatzu |
| Organization name |
University of Cologne (UoC), Germany
|
| Department |
CECAD
|
| Street address |
Joseph-Stelzmann-Straße 26
|
| City |
Cologne |
| ZIP/Postal code |
50931 |
| Country |
Germany |
| |
|
| Platforms (1) |
| GPL6801 |
[GenomeWideSNP_6] Affymetrix Genome-Wide Human SNP 6.0 Array |
|
| Samples (113)
|
|
| This SubSeries is part of SuperSeries: |
| GSE107513 |
The molecular basis of T-PLL is an actionable perturbation of TCL1/ATM- and epigenetically instructed damage responses |
|
| Relations |
| BioProject |
PRJNA420391 |
Less...
More...