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

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

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.