PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma.
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Embargo End Date
ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2019-08-22
Date Accepted
2019-08-01
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.
Citation
Nature Communications, 2019, 10 (1), pp. 3790 -
Source Title
Nature Communications
Publisher
NATURE RESEARCH
ISSN
2041-1723
eISSN
2041-1723
2041-1723
2041-1723
Collections
Research Team
Glioma Team