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

Autor:	Fons NR; Department of Pathology, Yale University, New Haven, CT, 06520, USA.; Department of Therapeutic Radiology, Yale University, New Haven, CT, 06520, USA., Sundaram RK; Department of Therapeutic Radiology, Yale University, New Haven, CT, 06520, USA., Breuer GA; Department of Pathology, Yale University, New Haven, CT, 06520, USA.; Department of Therapeutic Radiology, Yale University, New Haven, CT, 06520, USA., Peng S; The Translational Genomics Research Institute (TGen), Phoenix, AZ, 85004, USA., McLean RL; Department of Therapeutic Radiology, Yale University, New Haven, CT, 06520, USA., Kalathil AN; Department of Therapeutic Radiology, Yale University, New Haven, CT, 06520, USA., Schmidt MS; Department of Biochemistry, University of Iowa, Iowa City, IA, 52242, USA., Carvalho DM; Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, UK., Mackay A; Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, UK., Jones C; Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, UK., Carcaboso ÁM; Institut de Recerca Sant Joan de Deu, Barcelona, 08950, Spain., Nazarian J; Children's National Health System, Washington, DC, 20010, USA., Berens ME; The Translational Genomics Research Institute (TGen), Phoenix, AZ, 85004, USA. mberens@tgen.org., Brenner C; Department of Biochemistry, University of Iowa, Iowa City, IA, 52242, USA. charles-brenner@uiowa.edu., Bindra RS; Department of Pathology, Yale University, New Haven, CT, 06520, USA. ranjit.bindra@yale.edu.; Department of Therapeutic Radiology, Yale University, New Haven, CT, 06520, USA. ranjit.bindra@yale.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2019 Aug 22; Vol. 10 (1), pp. 3790. Date of Electronic Publication: 2019 Aug 22.
DOI:	10.1038/s41467-019-11732-6
Abstrakt:	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.
Databáze:	MEDLINE
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