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| 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 [murine SNP array] |
| Organism |
Mus musculus |
| 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.
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| Overall design |
Murine T-cell leukemia. Sample preparation: We hybridized DNA samples (QIAamp DNA Kit, Qiagen) onto the Affymetrix MOUSEDIVm520650 chip. We compared 4 controls (DNA isolated from normal liver tissues of age- and background-matched wild-type mice) to 3 ‘chronic phase’ and 5 ‘exponential phase’ (defining features in 4.2) splenic isolates from T-cell leukemia / lymphoma bearing Lckpr-hTCL1A+/- mice.
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| Citation(s) |
29449575 |
| |
| Submission date |
Nov 29, 2017 |
| Last update date |
Feb 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 |
| |
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| Platforms (1) |
| GPL13147 |
[MOUSEDIVm520650] Affymetrix Mouse Diversity Genotyping Array |
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| Samples (12)
|
| GSM2870349 |
Lckpr-TCL1A+/- T-cells; ‘exponential phase’ 1 |
| GSM2870350 |
Lckpr-TCL1A+/- T-cells; ‘exponential phase’ 2 |
| GSM2870351 |
Lckpr-TCL1A+/- T-cells; ‘exponential phase’ 3 |
| GSM2870352 |
Lckpr-TCL1A+/- T-cells; ‘exponential phase’ 4 |
| GSM2870353 |
Lckpr-TCL1A+/- T-cells; ‘exponential phase’ 5 |
| GSM2870354 |
Lckpr-TCL1A+/- T-cells; ‘chronic phase’ 1 |
| GSM2870355 |
Lckpr-TCL1A+/- T-cells; ‘chronic phase’ 2 |
| GSM2870356 |
Lckpr-TCL1A+/- T-cells; ‘chronic phase’ 3 |
| GSM2870357 |
age-matched C57BL/6 (wild-type) mice 1 |
| GSM2870358 |
age-matched C57BL/6 (wild-type) mice 2 |
| GSM2870359 |
age-matched C57BL/6 (wild-type) mice 3 |
| GSM2870360 |
age-matched C57BL/6 (wild-type) mice 4 |
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| 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 |
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| Relations |
| BioProject |
PRJNA420386 |
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