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TP53 wild type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE189152 | GEO | 2021/11/20

REPOSITORIES: GEO

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TP53 wild type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist

Project description:TP53 wild type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist

| PRJNA781664 | ENA

TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist

Project description: Not available

| S-EPMC8565061 | biostudies-literature

PPM1D Mutations Silence NAPRT Gene Expression and Confer NAMPT Inhibitor Sensitivity in Glioma

Project description:Genome wide DNA methylation profiling of wild type and PPM1D mutant astrocytes and patient-derived DIPG cell lines. The Illumina Human EPIC Bead Array (850k) platform was used to obtain methylation beta values of over 850k CpG sites throughout the genome across a panel of DIPG cell lines.

2019-07-12 | GSE134165 | GEO

RNA sequencing of tumors from PPM1D transgenic mouse model

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.

2020-12-31 | GSE157769 | GEO

Characterizing TP53 and PPM1D mutations as resistance drivers to radiation therapy in Diffuse Intrinsic Pontine Gliomas

Project description:Characterizing TP53 and PPM1D mutations as resistance drivers to radiation therapy in Diffuse Intrinsic Pontine Gliomas

| PRJNA714986 | ENA

Characterizing TP53 and PPM1D mutations as resistance drivers to radiation therapy in Diffuse Intrinsic Pontine Gliomas

Project description:Characterizing TP53 and PPM1D mutations as resistance drivers to radiation therapy in Diffuse Intrinsic Pontine Gliomas

| PRJNA714988 | ENA

SOD1 is a synthetic lethal target in PPM1D-mutant leukemia cells

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.

2024-04-15 | GSE240874 | GEO

Potent anti-tumor efficacy of palbociclib in H3K27M-mutant diffuse intrinsic pontine glioma

Project description:Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain cancer without cure. DIPG has high percentage histone mutation at K27M on histone H3 locus, which is believed to be one of the drivers of the tumorigenesis. Dysregulation of G1/S cell cycle checkpoint is more enriched in the H3.3K27M mutant subgroup. In this study, we reported that palbociclib (PD0332991), a specific and cytostatic inhibitor of CDK4/6, effectively suppresses the growth of DIPG cells in vitro and in vivo. We established patient derived cell lines from treatment-naïve specimens, which all have H3.3K27M mutation. And our DIPG cell lines with H3.3K27M mutation have high CDK4/6 expression. Then, we showed that depletion of CDK4 or CDK6 inhibits DIPG cells growth and blocks G1/S transition. Furthermore, palbociclib effectively repressed all 8 cell lines self-renewal, proliferation and cell cycle progression from G1 to S phase in vitro. Transcriptome analysis showed that palbociclib not only blocks G1/S transition, it also blocks other oncogenic targets such as Myc. Finally, palbociclib activity was assayed in vivo against DIPG orthotropic xenografts to demonstrate the high efficiency of blocking tumor growth. Our findings revealed that palbociclib could be the therapy strategy for DIPG.

2019-06-20 | GSE115976 | GEO

DNA sequencing of human nontransformed retinal pigment epithelia RPE-PPM1D-T2 cells carrying a truncating mutation in exon 6 of the PPM1D

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

Substrate spectrum of PPM1D in the cellular response to DNA double strand breaks

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

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