Dataset Information

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

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			Action	DRS
	GSE107510_RAW.tar	Raw
	GSE107510_quant-norm.pm-only.brlmm-p.call.txt.gz	Txt
	GSE107510_quant-norm.pm-only.brlmm-p.norm.txt.gz	Txt
	filelist.txt	Txt

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Publications

Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL.

Schrader A A Crispatzu G G Oberbeck S S Mayer P P Pützer S S von Jan J J Vasyutina E E Warner K K Weit N N Pflug N N Braun T T Andersson E I EI Yadav B B Riabinska A A Maurer B B Ventura Ferreira M S MS Beier F F Altmüller J J Lanasa M M Herling C D CD Haferlach T T Stilgenbauer S S Hopfinger G G Peifer M M Brümmendorf T H TH Nürnberg P P Elenitoba-Johnson K S J KSJ Zha S S Hallek M M Moriggl R R Reinhardt H C HC Stern M-H MH Mustjoki S S Newrzela S S Frommolt P P Herling M M

Nature communications 20180215 1

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]

PMID: 29449575

Similar Datasets

Project description: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): Illumina HumanHT‑12 v4 BeadChip arrays (n=70 cases) for gene expression profiling (GEP). CD3+ pan T-cells isolated from peripheral blood (PB) of healthy donors with a similar age-median were used as “normal” controls for GEP (n=10). The isolation strategy of PB tumor cells and matched same-sample germline controls from PB mononuclear cells (PBMCs) of T-PLL patients employed a two-step magnetic separation (MACS columns) process: (1) Positive enrichment of T-PLL tumor cells: magnetic beads bound to anti-CD4 or anti-CD8 antibodies (Microbeads, Miltenyi Biotec) and LS Columns (Miltenyi Biotec) were used. The specificity of beads was selected according to the individual immunophenotype. (2) Depletion of residual T-PLL cells from the flow-through designated as normal control: Depletion Columns (LD, Miltenyi Biotec) were used to remove residual CD4 or CD8 positive cells from the flow-through obtained from step 1. For further details, see Methods section.

Project description:Protooncogene T-cell leukemia 1 (TCL1), which is implicated in human T-cell prolymphocytic leukemia (T-PLL), interacts with Akt and enhances its kinase activity, functioning as an Akt kinase co-activator. Two major isoforms of TCL1 Protooncogenes (TCL1 and TCL1b) are present adjacent to each other on human chromosome 14q.32. In human T-PLL, both TCL1 and TCL1b are activated by chromosomal translocation. Moreover, TCL1b-transgenic mice have never been created. Therefore, it remains unclear whether TCL1b itself, independent of TCL1, exhibits oncogenicity. In co-immunoprecipitation assays, both ectopic and endogenous TCL1b interacted with Akt. In in vitro Akt kinase assays, TCL1b enhanced Akt kinase activity in dose- and time-dependent manners. Bioinformatics approaches utilizing multiregression analysis, cluster analysis, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway mapping, Venn diagrams and Gene Ontology (GO) demonstrated that TCL1b showed highly homologous gene-induction signatures similar to Myr-Akt or TCL1. TCL1b exhibited oncogenicity in in vitro colony-transformation assay. Further, two independent lines of ?-actin promoter-driven TCL1b-transgenic mice developed angiosarcoma on the intestinal tract. Angiosarcoma is a rare form of cancer in humans with poor prognosis. Using immunohistochemistry, 11 out of 13 human angiosarcoma samples were positively stained with both anti-TCL1b and anti-phospho-Akt antibodies. Consistently, in various cancer tissues, 69 out of 146 samples were positively stained with anti-TCL1b, out of which 46 were positively stained with anti-phospho-Akt antibodies. Moreover, TCL1b structure-based inhibitor 'TCL1b-Akt-in' inhibited Akt kinase activity in in vitro kinase assays and PDGF (platelet-derived growth factor)-induced Akt kinase activities-in turn, 'TCL1b-Akt-in' inhibited cellular proliferation of sarcoma. The current study disclosed TCL1b bears oncogenicity and hence serves as a novel therapeutic target for human neoplastic diseases.