Related Experiment Video
Updated: Jan 20, 2026
Primary Orthotopic Glioma Xenografts Recapitulate Infiltrative Growth and Isocitrate Dehydrogenase I Mutation
Published on: January 14, 2014
PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma
Nathan R Fons1,2, Ranjini K Sundaram2, Gregory A Breuer1,2
1Department of Pathology, Yale University, New Haven, CT, 06520, USA.
Abstract:
Pediatric high-grade gliomas are among the deadliest of childhood cancers due to limited knowledge of early driving events in their gliomagenesis and the lack of effective therapies available. In this study, we investigate the oncogenic role of PPM1D, a protein phosphatase often found truncated in pediatric gliomas such as DIPG, and uncover a synthetic lethal interaction between PPM1D mutations and nicotinamide phosphoribosyltransferase (NAMPT) inhibition. Specifically, we show that mutant PPM1D drives hypermethylation of CpG islands throughout the genome and promotes epigenetic silencing of nicotinic acid phosphoribosyltransferase (NAPRT), a key gene involved in NAD biosynthesis. Notably, PPM1D mutant cells are shown to be sensitive to NAMPT inhibitors in vitro and in vivo, within both engineered isogenic astrocytes and primary patient-derived model systems, suggesting the possible application of NAMPT inhibitors for the treatment of pediatric gliomas. Overall, our results reveal a promising approach for the targeting of PPM1D mutant tumors, and define a critical link between oncogenic driver mutations and NAD metabolism, which can be exploited for tumor-specific cell killing.
Insights
Pediatric high-grade gliomas are deadly childhood cancers. This study reveals that inhibiting NAMPT may effectively treat PPM1D-mutant gliomas by targeting NAD metabolism.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Pediatric high-grade gliomas (HGGs) are aggressive childhood brain tumors with poor prognoses.
- Limited understanding of gliomagenesis drivers and effective therapies hinders treatment for HGGs.
Purpose of the Study:
- Investigate the oncogenic role of PPM1D mutations in pediatric gliomas.
- Identify therapeutic vulnerabilities associated with PPM1D mutations.
Main Methods:
- Examined the function of truncated PPM1D in gliomagenesis.
- Assessed the impact of PPM1D mutations on epigenetic regulation and NAD biosynthesis.
- Tested sensitivity to NAMPT inhibitors in vitro and in vivo using cell and patient-derived models.
Main Results:
- Mutant PPM1D promotes genome-wide hypermethylation and silences NAPRT, a key NAD biosynthesis gene.
- PPM1D-mutant pediatric glioma cells exhibit sensitivity to NAMPT inhibition.
- NAMPT inhibitors show efficacy in both engineered and patient-derived models.
Conclusions:
- PPM1D mutations create a synthetic lethal interaction with NAMPT inhibition in pediatric gliomas.
- Targeting NAD metabolism via NAMPT inhibitors offers a potential therapeutic strategy for PPM1D-mutant gliomas.
- This study defines a link between oncogenic drivers and NAD metabolism for targeted cancer cell killing.
More Related Videos
Related Concept Videos
01:09Mutation, Gene Flow, and Genetic Drift
01:42What is Gene Expression?
Gene expression is the process in which DNA directs the synthesis of functional products, that is, proteins. Cells can regulate gene expression at various stages. It allows organisms to generate different cell types and enables cells to adapt to internal and external factors.
Genetic Information Flows from DNA to RNA to Protein
A gene is a stretch of DNA that serves as the blueprint for functional RNAs and proteins. Since DNA is made up of nucleotides and proteins consist of amino...
01:36What is Gene Expression?
01:58Cell Specific Gene Expression
02:35Chromatin Position Affects Gene Expression
Topologically Associated Domains (TADs)
The 3-dimensional positioning of chromatin in the nucleus influences the...
02:51mRNA Stability and Gene Expression
Cis-acting Elements involved in mRNA stability