Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, with approximately 25% of DIPGs harboring activating ACVR1 mutations that commonly co-associate with H3.1K27M mutations. Here we show that in vitro expression of ACVR1 R206H with and without H3.1K27M upregulates mesenchymal markers and activates Stat3 signaling. In vivo expression of ACVR1 R206H or G328V with H3.1K27M and p53 deletion induces glioma-like lesions but is not sufficient for full gliomagenesis. However, in combination with PDGFA signaling, ACVR1 R206H and H3.1K27M significantly decrease survival and increase tumor incidence. Treatment of ACVR1 R206H mutant DIPGs with exogenous Noggin or the ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to LDN212854 treatment. Together, our results demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile partly due to Stat3 activation, and identify LDN212854 as a promising compound to treat DIPG.

弥漫性脑桥脑胶质瘤 (DIPG) 是一种无法治愈的小儿脑肿瘤，大约 25% 的 DIPG 具有激活的ACVR1突变，通常与 H3.1K27M 突变相关。在这里，我们显示ACVR1 R206H的体外表达有和没有 H3.1K27M 上调间充质标记并激活 Stat3 信号。具有 H3.1K27M 和 p53 缺失的ACVR1 R206H 或 G328V的体内表达诱导神经胶质瘤样病变，但不足以完全发生神经胶质瘤。然而，结合 PDGFA 信号，ACVR1 R206H 和 H3.1K27M 显着降低存活率并增加肿瘤发生率。用外源头蛋白或ACVR1处理ACVR1 R206H 突变体 DIPG抑制剂 LDN212854 显着延长了存活期，人类ACVR1突变体 DIPG 细胞系也对 LDN212854 处理敏感。总之，我们的结果表明ACVR1 R206H 和 H3.1K27M 促进肿瘤起始，加速胶质瘤生成，部分由于 Stat3 激活促进间充质分布，并将 LDN212854 确定为治疗 DIPG 的有前途的化合物。