Department of Pathology, Yale University, New Haven, CT, 06520, USA.
Department of Therapeutic Radiology, Yale University, New Haven, CT, 06520, USA.
Nat Commun. 2019 Aug 22;10(1):3790. doi: 10.1038/s41467-019-11732-6.
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.
小儿高级别神经胶质瘤是儿童癌症中最致命的癌症之一，这是由于人们对其神经发生过程中的早期驱动事件知之甚少，以及缺乏有效的治疗方法。在这项研究中，我们研究了 PPM1D 的致癌作用，PPM1D 是一种蛋白磷酸酶，在 DIPG 等小儿神经胶质瘤中经常发现截短，并且发现 PPM1D 突变与烟酰胺磷酸核糖转移酶（NAMPT）抑制之间存在合成致死性相互作用。具体来说，我们表明突变 PPM1D 驱动整个基因组中 CpG 岛的过度甲基化，并促进烟碱酸磷酸核糖基转移酶（NAPRT）的表观遗传沉默，NAPRT 是 NAD 生物合成中关键的基因。值得注意的是，在体外和体内，包括工程同基因神经胶质瘤和原发性患者来源的模型系统中，PPM1D 突变细胞对 NAMPT 抑制剂敏感，这表明 NAMPT 抑制剂可能应用于小儿神经胶质瘤的治疗。总的来说，我们的结果揭示了针对 PPM1D 突变肿瘤的有前途的方法，并定义了致癌驱动突变与 NAD 代谢之间的关键联系，这可以用于肿瘤特异性细胞杀伤。
