Exome seuencing of tumors from PPM1D transgenic mouse model
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB40261 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR4571600_1.fastq.gz | Fastqsanger.gz | |||
| ERR4571600_2.fastq.gz | Fastqsanger.gz | |||
| ERR4571610_1.fastq.gz | Fastqsanger.gz | |||
| ERR4571610_2.fastq.gz | Fastqsanger.gz | |||
| ERR4571601_1.fastq.gz | Fastqsanger.gz |
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Project description:The majority of cancers harbor alterations of the tumor suppressor TP53. However, childhood cancers, including unfavorable neuroblastoma, often lack TP53 mutations despite frequent loss of p53 function, suggesting alternative p53 inactivating mechanisms. Our study show that frequent gain of the p53-regulating gene PPM1D at chromosome 17q22.3 is linked to aggressive tumors and poor prognosis in neuroblastoma. A PPM1D transgenic mouse model develops cancers phenotypically and genetically similar to tumors arising in mice with dysfunctional p53 when subjected to low-dose irradiation. Tumors include T-cell lymphomas harboring Notch1- and Pten-mutations, adenocarcinomas and PHOX2B-expressing neuroblastomas, therey establishing PPM1D as a bona fide oncogene in wtTP53 cancer and childhood neuroblastoma. Pharmacological inhibition of WIP1 suppressed the growth of neural tumors in nude mice, proposing WIP1 as a therapeutic target in neural childhood tumors.
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Project description:RNA sequencing of tumors from PPM1D transgenic mouse model
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Project description:The role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genomes sequences of 170 pediatric high-grade gliomas and find that truncating mutations in PPM1D that increase the stability of its phosphatase are clonal driver events in 11% of DMGs and are enriched in primary pontine tumors. Through the development of novel DMG mouse models, we show that PPM1D mutations potentiate gliomagenesis and that PPM1D activity is required for in vivo oncogenesis. Finally, we applied integrative phosphoproteomic and functional genomics assays and found that the oncogenic effects of PPM1D truncation converge on regulators of cell cycle, DNA damage response, and p53 pathways, revealing therapeutic vulnerabilities including MDM2 inhibition. Together, these findings highlight PPM1D mutations to represent a targetable driver of pediatric gliomas.
2021-07-11 | GSE179813 | GEO
Project description:Human nontransformed retinal pigment epithelia RPE-PPM1D-T2 cells carrying a truncating mutation in exon 6 of the PPM1D were exposed to ionising radiation (3 Gy) and subsequently were grown in semisolid media for 8 weeks. Six spheroid clones (RPE-PPM1D-T2-SA clones 1-6) were recovered and then were cultivated in adherent conditions. DNA was isolated from asynchronically growing parental RPE-PPM1D-T2 and transformed RPE-PPM1D-T2-SA-1 to 6 cells and was subjected to whole exome sequencing. DNA sequencing libraries were prepared using KAPA EvoPlus Kit (Roche) and were sequenced on the NovaSeq 6000 system using NovaSeq S1 Reagent Kit v1.5, 200 cycles (Illumina) with mean coverage >35 DNA samples, respectively. DNA fastq files were mapped to the hg19 reference using Novoalign (novoalign_2.08.03). PCR duplicates were removed from the BAM files using Picard Tools (picard-tools 1.129), and variant calling was performed using GATK HaplotypeCaller (3.8). Copy number variations (CNV) were analyzed using CNVkit version 0.7.4. Areas with median coverage >20 were included in the analysis. RNA fastq files were mapped to the hg19 reference using STAR (STAR-2.5.2b). The PCR duplicates were removed using Picard Tools (picard-tools 1.129).
2024-04-05 | E-MTAB-13923 | biostudies-arrayexpress
Project description:PPM1D (also known as WIP1) is a p53-regulated protein phosphatase that modulates the DNA damage response (DDR) by dephosphorylation of DDR proteins. Amplification of PPM1D gene or gain-of-function mutations are commonly found in cancer. Here, we employed chemical inhibition of PPM1D and quantitative mass spectrometry-based phosphoproteomics to identify the substrates of PPM1D upon induction of DNA double strand breaks (DSBs) by topoisomerase II poison etoposide. We identified 73 putative PPM1D substrates that are involved in DNA repair, regulation of transcription and RNA processing. One third of DSB-induced S/TQ phosphorylation sites are dephosphorylated by PPM1D, demonstrating that PPM1D only partially counteracts ATM/ATR/DNA-PK signaling. PPM1D-targeted phosphorylation sites are found in a specific amino acid sequence motif that is characterized by glutamic acid residues, high intrinsic disorder and poor evolutionary conservation. We identified a functionally uncharacterized protein Kanadaptin as ATM and PPM1D substrate upon DSB induction. We propose that PPM1D plays a role during the response to DSBs formation by regulating the phosphorylation of DNA- and RNA-binding proteins in intrinsically disordered regions.
2022-09-06 | PXD035420 | Pride
Project description:Human nontransformed retinal pigment epithelia RPE-PPM1D-T2 cells carrying a truncating mutation in exon 6 of the PPM1D were exposed to ionising radiation (3 Gy) and subsequently were grown in semisolid media for 8 weeks. Six spheroid clones (RPE-PPM1D-T2-SA clones 1-6) were recovered and then were cultivated in adherent conditions. RNA was isolated from asynchronically growing parental RPE-PPM1D-T2 and transformed RPE-PPM1D-T2-SA-1 to 6 cells and was subjected to whole exome sequencing. RNA sequencing libraries were prepared using KAPA RNA HyperPrep Kit (Roche) and were sequenced on the NovaSeq 6000 system using NovaSeq S1 Reagent Kit v1.5, 200 cycles (Illumina) with mean coverage >120 for RNA samples, respectively. RNA fastq files were mapped to the hg19 reference using Novoalign (novoalign_2.08.03). PCR duplicates were removed from the BAM files using Picard Tools (picard-tools 1.129), and variant calling was performed using GATK HaplotypeCaller (3.8). RNA fastq files were mapped to the hg19 reference using STAR (STAR-2.5.2b). The PCR duplicates were removed using Picard Tools (picard-tools 1.129). All parts of RNAseq data analysis were conducted in R, version 4.3.2. and RNAseq read counts were normalized using R package DESeq2. Fold change (FC) and log2FC were calculated from normalized reads, nontransformed RPE-PPM1D-T1 cells were considered a reference. Significance of differential expression for each gene was evaluated by Fisher's t-test with simulated p-values and Holm's p-value correction for multiple comparisons.
2024-04-05 | E-MTAB-13933 | biostudies-arrayexpress
Project description:this study demonstrates the pre-clinical efcacy potential of RG7388 in the TP53 wild type/PPM1D mutant DIPG subgroup in the TP53 wild-type/PPM1D mutant DIPG subgroup mutant DIPG subgroup
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Project description:Using CRISPR/Cas9 dropout screening, we identified superoxide dismutase-1 (SOD1) as a genetic dependency specific to PPM1D-mutant leukemia cells. We found that the mutant cells exhibited a compromised response to oxidative stress that can be rescued with SOD1 inhibitors. PPM1D-mutant fcells also exhibit significant genomic instability, highlighting the essential role of SOD1 in safeguarding against oxidative stress and DNA damage.
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Project description:The p53 transcription factor is a master regulator of cellular stress responses restrained by repressors such as MDM2 and the phosphatase PPM1D. Activation of p53 with pharmacological inhibitors of its repressors is being tested in clinical trials for cancer therapy, but efficacy has been limited by poor induction of tumor cell death. We demonstrate that dual inhibition of MDM2 and PPM1D induces cell death in multiple cancer cell types via amplification of the p53 transcriptional program through the eIF2alpha -ATF4 pathway. PPM1D inhibition induces phosphorylation of eIF2alpha, ATF4 accumulation, and ATF4-dependent enhancement of p53-dependent transactivation upon MDM2 inhibition. Dual inhibition of p53 repressors depletes heme and induces HRI-dependent eIF2alpha phosphorylation. Pharmacological induction of eIF2alpha phosphorylation synergizes with MDM2 inhibition to induce cell death and halt tumor growth in mice. These results demonstrate that PPM1D inhibits both the p53 network and the integrated stress response controlled by eIF2alpha, with clear therapeutic implications.
2022-11-01 | GSE191148 | GEO
Project description:The p53 transcription factor is a master regulator of cellular stress responses restrained by repressors such as MDM2 and the phosphatase PPM1D. Activation of p53 with pharmacological inhibitors of its repressors is being tested in clinical trials for cancer therapy, but efficacy has been limited by poor induction of tumor cell death. We demonstrate that dual inhibition of MDM2 and PPM1D induces cell death in multiple cancer cell types via amplification of the p53 transcriptional program through the eIF2alpha -ATF4 pathway. PPM1D inhibition induces phosphorylation of eIF2alpha, ATF4 accumulation, and ATF4-dependent enhancement of p53-dependent transactivation upon MDM2 inhibition. Dual inhibition of p53 repressors depletes heme and induces HRI-dependent eIF2alpha phosphorylation. Pharmacological induction of eIF2alpha phosphorylation synergizes with MDM2 inhibition to induce cell death and halt tumor growth in mice. These results demonstrate that PPM1D inhibits both the p53 network and the integrated stress response controlled by eIF2alpha, with clear therapeutic implications.
2022-09-01 | GSE191149 | GEO