Meningioma represents the most common primary brain tumor in adults. Recently several non-NF2 mutations in meningioma have been identified and correlated with certain pathological subtypes, locations and clinical observations. Alterations of cellular pathways due to these mutations, however, have largely remained elusive. Here we report that the Krueppel like factor 4 (KLF4)-K409Q mutation in skull base meningiomas triggers a distinct tumor phenotype. Transcriptomic analysis of 17 meningioma samples revealed that KLF4K409Q mutated tumors harbor an upregulation of hypoxia dependent pathways. Detailed in vitro investigation further showed that the KLF4K409Q mutation induces HIF-1α through the reduction of prolyl hydroxylase activity and causes an upregulation of downstream HIF-1α targets. Finally, we demonstrate that KLF4K409Q mutated tumors are susceptible to mTOR inhibition by Temsirolimus. Taken together, our data link the KLF4K409Q mediated upregulation of HIF pathways to the clinical and biological characteristics of these skull base meningiomas possibly opening new therapeutic avenues for this distinct meningioma subtype.

中文翻译：

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KLF4K409Q突变的脑膜瘤显示增强的缺氧信号传导，并对mTORC1抑制剂治疗产生反应。

脑膜瘤是成人中最常见的原发性脑肿瘤。最近，已经鉴定出脑膜瘤中的几种非NF2突变，并与某些病理亚型，位置和临床观察结果相关。然而，由于这些突变而引起的细胞途径的改变在很大程度上仍然难以捉摸。在这里，我们报道颅骨脑膜瘤瘤中的Krueppel样因子4（KLF4）-K409Q突变触发了独特的肿瘤表型。对17个脑膜瘤样品的转录组学分析显示，KLF4K409Q突变的肿瘤具有缺氧依赖性途径的上调。详细的体外研究进一步表明，KLF4K409Q突变通过降低脯氨酰羟化酶活性诱导HIF-1α，并导致下游HIF-1α靶标上调。最后，我们证明了KLF4K409Q突变的肿瘤易受Temsirolimus抑制mTOR。综上所述，我们的数据将KLF4K409Q介导的HIF通路上调与这些颅底脑膜瘤的临床和生物学特征联系起来，可能为这种独特的脑膜瘤亚型开辟新的治疗途径。