Genomics

Dataset Information

35

The molecular basis of T-PLL is an actionable perturbation of TCL1/ATM- and epigenetically instructed damage responses [murine SNP array]


ABSTRACT: 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: 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.

INSTRUMENT(S): [MOUSEDIVm520650] Affymetrix Mouse Diversity Genotyping Array

SUBMITTER: Dr. Marco Herling 

PROVIDER: GSE107510 | GEO | 2017-11-30

SECONDARY ACCESSION(S): PRJNA420386

REPOSITORIES: GEO

Dataset's files

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GSE107510_RAW.tar Raw
GSE107510_quant-norm.pm-only.brlmm-p.call.txt.gz Txt
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Publications


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 sp  ...[more]

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