PPM1D mutations silence NAPRT gene\xa0expression and confer NAMPT inhibitor sensitivity in glioma

Nathan R Fons,Michael E Berens,Chris Jones,Diana M Carvalho,Ranjit S Bindra,Alan Mackay,Ángel M Carcaboso,Sen Peng,Aravind N Kalathil,Ryan L Mclean,Ranjini K Sundaram,Javad Nazarian,Gregory A Breuer,Charles Brenner,Mark S Schmidt

doi:10.1038/s41467-019-11732-6

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.

Highlights

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
Through a targeted synthetic lethal drug screen, we demonstrate that Phosphatase Mg2+/Mn2+ Dependent 1D (PPM1D) mutant astrocytes and patient-derived PPM1D mutant diffuse intrinsic pontine glioma (DIPG) lines are sensitive to treatment with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors
We show that this mutant PPM1D-induced NAMPT inhibitor sensitivity is driven by hypermethylation of CpG islands throughout the genome, and in particular, the epigenetic silencing of nicotinic acid phosphoribosyltransferase (NAPRT), a key gene involved in nicotinamide adenine dinucleotide (NAD) biosynthesis

Summary

Introduction

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. 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. We show that this mutant PPM1D-induced NAMPT inhibitor sensitivity is driven by hypermethylation of CpG islands throughout the genome, and in particular, the epigenetic silencing of nicotinic acid phosphoribosyltransferase (NAPRT), a key gene involved in nicotinamide adenine dinucleotide (NAD) biosynthesis. These findings provide important insights into the biological effects of truncating PPM1D mutations, and uncover unique vulnerabilities associated with enhanced PPM1D activity which can be exploited for the therapeutic intervention of mutant pediatric brain tumors

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Conclusion