Li H, Zhao X, Yan X, Jessen W J, Kim M-O, Dombi E, Liu P P, Huang G, Wu J
Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH, USA.
Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital University of Cincinnati, Cincinnati, OH, USA.
Oncogene. 2016 Mar 17;35(11):1468-74. doi: 10.1038/onc.2015.207. Epub 2015 Jun 15.
Neurofibromatosis type 1 (NF1) patients are predisposed to neurofibromas but the driver(s) that contribute to neurofibroma formation are not fully understood. By cross comparison of microarray gene lists on human neurofibroma-initiating cells and developed neurofibroma Schwann cells (SCs) we identified RUNX1 overexpression in human neurofibroma initiation cells, suggesting RUNX1 might relate to neurofibroma formation. Immunostaining confirmed RUNX1 protein overexpression in human plexiform neurofibromas. Runx1 overexpression was confirmed in mouse Schwann cell progenitors (SCPs) and mouse neurofibromas at the messenger RNA and protein levels. Genetic inhibition of Runx1 expression by small hairpin RNA or pharmacological inhibition of Runx1 function by a Runx1/Cbfβ interaction inhibitor, Ro5-3335, decreased mouse neurofibroma sphere number in vitro. Targeted genetic deletion of Runx1 in SCs and SCPs delayed mouse neurofibroma formation in vivo. Mechanistically, loss of Nf1 increased embryonic day 12.5 Runx1(+)/Blbp(+) progenitors that enable tumor formation. These results suggest that Runx1 has an important role in Nf1 neurofibroma initiation, and inhibition of RUNX1 function might provide a novel potential therapeutic treatment strategy for neurofibroma patients.
1型神经纤维瘤病（NF1）患者易患神经纤维瘤，但导致神经纤维瘤形成的驱动因素尚未完全明确。通过对人类神经纤维瘤起始细胞和已形成的神经纤维瘤雪旺细胞（SCs）的基因芯片列表进行交叉比较，我们发现人类神经纤维瘤起始细胞中RUNX1过表达，这表明RUNX1可能与神经纤维瘤的形成有关。免疫染色证实RUNX1蛋白在人类丛状神经纤维瘤中过表达。在小鼠雪旺细胞前体细胞（SCPs）和小鼠神经纤维瘤中，在信使RNA和蛋白质水平均证实了Runx1过表达。通过小发夹RNA对Runx1表达进行基因抑制，或使用Runx1/Cbfβ相互作用抑制剂Ro5-3335对Runx1功能进行药理学抑制，均可降低体外培养的小鼠神经纤维瘤球的数量。在SCs和SCPs中对Runx1进行靶向基因缺失可延缓体内小鼠神经纤维瘤的形成。从机制上讲，Nf1的缺失增加了胚胎第12.5天能够形成肿瘤的Runx1(+)/Blbp(+)前体细胞。这些结果表明，Runx1在Nf1神经纤维瘤起始中起重要作用，抑制RUNX1功能可能为神经纤维瘤患者提供一种新的潜在治疗策略。
