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. 2019 Aug 22;10:3790. doi: 10.1038/s41467-019-11732-6

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 2 — Mutant PPM1D-induced NAPRT deficiency drives sensitivity to NAMPT inhibition. a Graphic model of enzymes (red) and metabolites (black) involved in NAD biosynthesis. NA nicotinic acid, NAAD nicotinic acid adenine dinucleotide, NAD nicotinamide adenine dinucleotide, NADP nicotinamide adenine dinucleotide phosphate, NAM nicotinamide, NAMN nicotinic acid mononucleotide, NAR nicotinic acid riboside, NMN nicotinamide mononucleotide, NR nicotinamide riboside, QA quinolinic acid, Trp tryptophan. b Heatmap of NAD-related metabolites in parental and two different PPM1D^trnc. astrocyte cell lines. c NAD quantification in wild type and PPM1D^trnc. astrocytes (n = 3 biological independent samples, ****p < 0.0001 by Student’s T test). d Relative fold change in NAD levels post 10 nM FK866 treatment (n = 3 biological independent samples, ***p < 0.001 by Student’s T test). e Bliss 3D surface plot modeling the antagonistic effects of NR on FK866 treatment in PPM1D^trnc. astrocytes. f Cell viability analysis of parental astrocytes treated with either scrambled control (scrbl) or NAPRT siRNAs, followed by treatment with FK866 (n = 2 biological independent samples, ****p < 0.0001 by Student’s T test). g Immunoblot of isogenic astrocytes., and astrocytes stably-overexpressing WT and mutant PPM1D (OE^FL and OE^trnc., respectively). Full length (full arrow), CRISPR-modified (black arrowhead), and ectopic mutant (white arrowhead) sizes of PPM1D displayed. h Viability assessment of isogenic astrocytes and stable NAPRT-expressing PPM1D^trnc. astrocytes (PPM1D^trnc. + NAPRT), after FK866 treatment (n = 4 biological independent samples, ***p < 0.001, ****p < 0.0001 by Student’s T test). i Immunoblot of previously described wild type and PPM1D mutant astrocytes, and patient-derived, SU-DIPG cell lines. j Viability assessment of SU-DIPG cell lines post 120 h treatment with FK866 (n = 3 biological independent samples). k Representative images from spheroid cultures in (j), untreated or treated with 10 nM FK866. All error bars represent standard deviation of the mean