Cincinnati Children's Hospital Medical Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, University of Cincinnati, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
Department of Cancer and Cell Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Sci Adv. 2019 Apr 24;5(4):eaau8389. doi: 10.1126/sciadv.aau8389. eCollection 2019 Apr.
Patients with neurofibromatosis type 1 (NF1) are predisposed to develop neurofibromas, but the underlying molecular mechanisms of neurofibromagenesis are not fully understood. We showed dual genetic deletion of and in Schwann cells (SCs) and SC precursors delayed neurofibromagenesis and prolonged mouse survival. We identified peripheral myelin protein 22 () related to neurofibroma initiation. Knockdown of with short hairpin RNAs increased tumor-derived sphere numbers and enabled significantly more neurofibroma-like microlesions on transplantation. Conversely, overexpression of in mouse neurofibroma SCs decreased cell proliferation. Mechanistically, RUNX1/3 regulated alternative promoter usage and induced levels of protein expression of to control SC growth. Last, pharmacological inhibition of RUNX/core-binding factor β (CBFB) activity significantly reduced neurofibroma volume in vivo. Thus, we identified a signaling pathway involving RUNX1/3 suppression of in neurofibroma initiation and/or maintenance. Targeting disruption of RUNX/CBFB interaction might provide a novel therapy for patients with neurofibroma.
患者患有神经纤维瘤病 1 型（NF1）易发生神经纤维瘤，但神经纤维瘤发生的潜在分子机制尚不完全清楚。我们显示 Schwann 细胞（SCs）和 SC 前体细胞中 的双基因缺失延迟了神经纤维瘤的发生并延长了小鼠的存活时间。我们鉴定了与神经纤维瘤起始相关的外周髓鞘蛋白 22（）。短发夹 RNA 敲低 增加了肿瘤衍生球体的数量，并使移植后出现更多的神经纤维瘤样微损伤。相反，在小鼠神经纤维瘤 SC 中过表达 可降低细胞增殖。从机制上讲，RUNX1/3 调节替代启动子的使用，并诱导 的蛋白表达水平，以控制 SC 生长。最后，RUNX/核心结合因子 β（CBFB）活性的药理学抑制显著减少了体内神经纤维瘤的体积。因此，我们鉴定了一条涉及 RUNX1/3 抑制神经纤维瘤起始和/或维持的信号通路。靶向破坏 RUNX/CBFB 相互作用可能为神经纤维瘤患者提供一种新的治疗方法。
