加拿大多伦多大学Tak W. Mak和Jerome Fortin团队合作取得一项新突破。他们提出突变ACVR1阻止小胶质细胞分化，以驱动小儿胶质瘤的发生。这一研究成果发表在2020年3月5日出版的《癌细胞》杂志上。

使用小鼠模型，他们证明Acvr1 G328V可以阻止少突胶质细胞系的分化，并与Hist1h3b K27M和Pik3ca H1047R协同产生高级扩散神经胶质瘤。从机理上讲，Acvr1 G328V上调控制分化和DIPG细胞适应性的转录因子。此外，他们表征E6201作为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，他们的结果描述了ACVR1突变的致癌作用机制，并提出了DIPG的治疗策略。

据悉，扩散脑桥神经胶质瘤（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尚不清楚。

附：英文原文

Title: Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas

Author: Jerome Fortin, Ruxiao Tian, Ida Zarrabi, Graham Hill, Eleanor Williams, Gonzalo Sanchez-Duffhues, Midory Thorikay, Parameswaran Ramachandran, Robert Siddaway, Jong Fu Wong, Annette Wu, Lorraine N. Apuzzo, Jillian Haight, Annick You-Ten, Bryan E. Snow, Andrew Wakeham, David J. Goldhamer, Daniel Schramek, Alex N. Bullock, Peter ten Dijke, Cynthia Hawkins, Tak W. Mak

Issue&Volume: 2020-03-05

Abstract: Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors forwhich there is currently no effective treatment. Some of these tumors combine gain-of-functionmutations 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 Acvr1G328V arrests the differentiation of oligodendroglial lineage cells, and cooperates withHist1h3bK27M and Pik3caH1047R to generate high-grade diffuse gliomas. Mechanistically, Acvr1G328V upregulates transcription factors which control differentiation and DIPG cell fitness.Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrateits efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.

DOI: 10.1016/j.ccell.2020.02.002

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30091-X