PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma

• Published in: Nature communications Vol. 10; no. 1; pp. 3790 - 10
• Main Authors: Fons, Nathan R., Sundaram, Ranjini K., Breuer, Gregory A., Peng, Sen, McLean, Ryan L., Kalathil, Aravind N., Schmidt, Mark S., Carvalho, Diana M., Mackay, Alan, Jones, Chris, Carcaboso, Ángel M., Nazarian, Javad, Berens, Michael E., Brenner, Charles, Bindra, Ranjit S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.08.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 38/109; 38/15; 38/77; 45/23; 45/41; 45/70; 59/5; 631/67/1922; 631/67/395; 631/67/68/2486; 96/1; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Astrocytes; Biosynthesis; Brain Stem Neoplasms - drug therapy; Brain Stem Neoplasms - genetics; Brain Stem Neoplasms - pathology; Brain tumors; Cell Line, Tumor; Child; Children; CpG islands; Cytokines - antagonists & inhibitors; Diffuse Intrinsic Pontine Glioma - drug therapy; Diffuse Intrinsic Pontine Glioma - genetics; Diffuse Intrinsic Pontine Glioma - pathology; DNA Methylation; Epigenetic Repression; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genomes; Glioma; Humanities and Social Sciences; Humans; Inhibitors; Mice; multidisciplinary; Mutation; NAD; Nicotinamide; Nicotinamide phosphoribosyltransferase; Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors; Nicotinamide Phosphoribosyltransferase - genetics; Nicotinamide Phosphoribosyltransferase - metabolism; Nicotinic acid; Pediatrics; Phosphoribosyltransferase; Pons - cytology; Pons - pathology; Primary Cell Culture; Protein phosphatase; Protein Phosphatase 2C - genetics; Protein Phosphatase 2C - metabolism; Science; Science (multidisciplinary); Synthetic Lethal Mutations; Tumors; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11732-6

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. Mutations in the Protein Phosphatase PPM1D are oncogenic in certain cancers including diffuse intrinsic pontine glioma (DIPG). Here, the authors show that PPM1D mutations in DIPG induce the silencing of the nicotinic acid phosphoribosyltransferase gene and display synthetic lethality with nicotinamide phosphoribosyltransferase inhibitors.