Department of Pediatrics, Northwestern University, Chicago, IL, 60611, USA.
GI Oncology Research Unit, Duke Cancer Institute, Duke University, Durham, NC, 27710, USA.
Nat Commun. 2019 Mar 4;10(1):1023. doi: 10.1038/s41467-019-08823-9.
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.
弥漫性内在脑桥神经胶质瘤（DIPG）是一种无法治愈的儿童脑肿瘤，约 25%的 DIPG 存在激活的 ACVR1 突变，通常与 H3.1K27M 突变共同存在。在这里，我们展示了体外表达 ACVR1 R206H 及其与 H3.1K27M 的共表达会上调间充质标志物并激活 Stat3 信号通路。体内表达 ACVR1 R206H 或 G328V 及其与 H3.1K27M 和 p53 缺失诱导类胶质瘤病变，但不足以完全形成胶质瘤。然而，与 PDGFA 信号通路联合表达时，ACVR1 R206H 和 H3.1K27M 显著降低存活率并增加肿瘤发生率。用外源性 Noggin 或 ACVR1 抑制剂 LDN212854 治疗 ACVR1 R206H 突变的 DIPG 可显著延长生存期，人类 ACVR1 突变的 DIPG 细胞系也对 LDN212854 治疗敏感。总之，我们的结果表明，ACVR1 R206H 和 H3.1K27M 促进肿瘤起始，加速胶质瘤发生，促进间充质表型，部分原因是 Stat3 激活，并确定 LDN212854 是治疗 DIPG 的一种有前途的化合物。
