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| Status |
Public on Nov 28, 2017 |
| Title |
The molecular basis of T-PLL is an actionable perturbation of TCL1/ATM- and epigenetically instructed damage responses [murine gene expression array] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by 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 |
GEP of TCL1A-induced murine T-cell leukemia (enriched splenic CD8+ T-cells) using Affymetrix GeneChip Mouse Gene 1.0 ST Arrays. Purified splenic CD3+ pan-T-cells isolated from C57BL/6 mice (3 arrays from T-cell pools of 3 mice each (total n=9) were used as matched controls.
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| Citation(s) |
29449575 |
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| Submission date |
Nov 27, 2017 |
| Last update date |
Mar 04, 2019 |
| Contact name |
Giuliano Crispatzu |
| Organization name |
University of Cologne (UoC), Germany
|
| Department |
CECAD
|
| Street address |
Joseph-Stelzmann-Straße 26
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| City |
Cologne |
| ZIP/Postal code |
50931 |
| Country |
Germany |
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| Platforms (1) |
| GPL6246 |
[MoGene-1_0-st] Affymetrix Mouse Gene 1.0 ST Array [transcript (gene) version] |
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| Samples (11)
|
| GSM2865844 |
Lckpr-TCL1A+/- T-cells; exponential phase 1 |
| GSM2865845 |
Lckpr-TCL1A+/- T-cells; exponential phase 2 |
| GSM2865846 |
Lckpr-TCL1A+/- T-cells; exponential phase 3 |
| GSM2865847 |
Lckpr-TCL1A+/- T-cells; exponential phase 4 |
| GSM2865848 |
Lckpr-TCL1A+/- T-cells; exponential phase 5 |
| GSM2865849 |
Lckpr-TCL1A+/- T-cells; chronic phase 1 |
| GSM2865850 |
Lckpr-TCL1A+/- T-cells; chronic phase 2 |
| GSM2865851 |
Lckpr-TCL1A+/- T-cells; chronic phase 3 |
| GSM2865852 |
age-matched C57BL/6 (wild-type) mice 1 |
| GSM2865853 |
age-matched C57BL/6 (wild-type) mice 2 |
| GSM2865854 |
age-matched C57BL/6 (wild-type) mice 3 |
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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 |
PRJNA419957 |
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