Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1^G328V arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3b^K27M and Pik3ca^H1047R to generate high-grade diffuse gliomas. Mechanistically, Acvr1^G328V upregulates transcription factors which control differentiation and DIPG cell fitness. Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.

弥漫性桥脑神经胶质瘤（DIPG）是侵袭性小儿脑肿瘤，目前尚无有效的治疗方法。这些肿瘤中的一些结合了ACVR1，PIK3CA和组蛋白H3编码基因中的功能获得性突变。ACVR1突变的致癌机制目前未知。使用小鼠模型，我们证明Acvr1 ^G328V可以阻止少突胶质细胞系的分化，并与Hist1h3b ^K27M和Pik3ca ^H1047R协同产生高度的弥散性神经胶质瘤。机械上，Acvr1 ^G328V上调控制分化和DIPG细胞适应性的转录因子。此外，我们将E6201表征为ACVR1和MEK1 / 2的双重抑制剂，并证明其对体内肿瘤细胞的功效。总的来说，我们的结果描述了ACVR1突变的致癌作用机理，并提出了DIPG的治疗策略。