PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma.
Date
2019-08-22Author
Fons, NR
Sundaram, RK
Breuer, GA
Peng, S
McLean, RL
Kalathil, AN
Schmidt, MS
Carvalho, DM
Mackay, A
Jones, C
Carcaboso, ÁM
Nazarian, J
Berens, ME
Brenner, C
Bindra, RS
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Animals
Antineoplastic Agents
Brain Stem Neoplasms
Cell Line, Tumor
Child
Cytokines
DNA Methylation
Diffuse Intrinsic Pontine Glioma
Epigenetic Repression
Female
Gene Expression Regulation, Neoplastic
Humans
Mice
Nicotinamide Phosphoribosyltransferase
Pons
Primary Cell Culture
Protein Phosphatase 2C
Synthetic Lethal Mutations
Xenograft Model Antitumor Assays
Research team
Glioma Team
Language
eng
Date accepted
2019-08-01
License start date
2019-08-22
Citation
Nature Communications, 2019, 10 (1), pp. 3790 -
Publisher
NATURE RESEARCH