Molecular mechanisms mediated by ACVR1 G328V and H3K27M in diffuse intrinsic pontine glioma biology

项目概要/摘要 弥漫性内在脑桥胶质瘤（DIPG）是一种最常见的脑肿瘤， 中位年龄为6-7岁的儿童，预后非常差。两个月后10%的存活率 年小于2年。肿瘤起源于脑桥，但具有高度侵袭性。由于其 敏感的位置和侵袭性，肿瘤不能手术切除。化疗 和放射是唯一的治疗选择;然而， found.因此，研究这种肿瘤的内在生物学对于设计改进的 分子靶向治疗该建议将利用从基因组中获得的信息， 尸检和活检组织的研究显示存在功能的复发性增益 ACVR 1突变和编码组蛋白H3的基因中的显性负性K27 M突变 变体，H3.3和H3.1。ACVR 1是丝氨酸-苏氨酸激酶跨膜信号 骨形态发生途径（BMP）的蛋白质转导;然而，目前尚不清楚如何进行 改变的BMP信号传导影响DIPG发病机制。显性负突变发生在 组蛋白H3.1和H3.3变体导致组蛋白H3 K27三重分布和全局丢失。 甲基化，从而影响基因表达。该提案将使用基因 工程化的免疫活性小鼠模型，以解决ACVR 1 G328 V的作用， 通常共表达H3.1 K27 M对DIPG发病机制的影响，并将寻求了解其 影响肿瘤对DNA损伤剂的反应。总之，纳入的研究 该提案将产生与ACVR 1和H3.1患者相关的新翻译数据 突变我们的研究结果将有助于设计未来治疗DIPG的靶向疗法。

Project Summary/Abstract Diffuse intrinsic pontine glioma (DIPG) is a brain tumor most commonly diagnosed in children of median age 6-7 and the prognosis is very poor. The ten percent survival after two years is less than 2 years. The tumor originates in the pons, but is highly invasive. Due to its sensitive location and invasive nature, the tumor cannot be removed surgically. Chemotherapy and radiation are the only treatment options; however no effective chemotherapy has been found. Thus, studying the intrinsic biology of this tumor is imperative for the design of improved molecularly targeted therapies. This proposal will utilize the information gained from genomic studies of autopsy and biopsy tissue that revealed the presence of recurrent gain of function mutations in ACVR1 and dominant negative K27M mutations in the genes encoding histone H3 variants, H3.3 and H3.1. ACVR1 is a serine-threonine kinase transmembrane signal transduction protein of the bone morphogenetic pathway (BMP); however, it is unknown how altered BMP signaling affects DIPG pathogenesis. The dominant negative mutation occurring in Histone H3.1 and H3.3 variants results in a global loss and redistribution of histone H3K27 tri- methylation which consequently affects gene expression. This proposal will use a genetically engineered immunocompetent mouse model to address the role of ACVR1 G328V and commonly co-expressed H3.1 K27M on DIPG pathogenesis and will seek to understand their impact on the tumor response to DNA damaging agents. In summary, the studies included in this proposal will generate novel translational data relevant to patients with ACVR1 and H3.1 mutations. Our results will aid in the design of future targeted therapies for treatment of DIPG.