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

Nathan R. Fons, Ranjini K. Sundaram, Gregory A. Breuer, Sen Peng, Ryan L. McLean, Aravind N. Kalathil, Mark S. Schmidt, Diana M. Carvalho, Alan Mackay, Chris Jones, Ángel M. Carcaboso, Javad Nazarian, Michael E. Berens (), Charles Brenner () and Ranjit S. Bindra ()
Additional contact information
Nathan R. Fons: Yale University
Ranjini K. Sundaram: Yale University
Gregory A. Breuer: Yale University
Sen Peng: The Translational Genomics Research Institute (TGen)
Ryan L. McLean: Yale University
Aravind N. Kalathil: Yale University
Mark S. Schmidt: University of Iowa
Diana M. Carvalho: Institute of Cancer Research
Alan Mackay: Institute of Cancer Research
Chris Jones: Institute of Cancer Research
Ángel M. Carcaboso: Institut de Recerca Sant Joan de Deu
Javad Nazarian: Children’s National Health System
Michael E. Berens: The Translational Genomics Research Institute (TGen)
Charles Brenner: University of Iowa
Ranjit S. Bindra: Yale University

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11732-6

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