Deciphering the pathogenesis of pediatric high-grade gliomas

破译儿童高级别胶质瘤的发病机制

• 批准号: 8976602
• 负责人: Guo-Min Li
• 金额: $ 12.08万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8976602
• 关键词: Accounting; Biological Assay; Brain Neoplasms; Cancer Detection; Cell Line; Cells; Childhood; Chromatin; Co-Immunoprecipitations; DNA; DNA Sequence; Detection; Disease; Exhibits; Genes; Genome; Genomic Instability; Glioblastoma; Glioma; Goals; Health; Histone H3; Histone H3.3; Human; Immunofluorescence Immunologic; Immunohistochemistry; Lead; Link; Maintenance; Malignant - descriptor; Malignant Childhood Neoplasm; Measures; Methyltransferase; Microsatellite Instability; Mismatch Repair; Molecular; Mutation; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Primary Brain Neoplasms; Proteins; Recruitment Activity; Resistance; System; Testing; Therapeutic; Tissues; Tumor Cell Line; genome sequencing; glioma cell line; improved; in vivo; molecular subtypes; neoplastic cell; novel marker; outcome forecast; research study; temozolomide; tumorigenesis; whole genome; young adult

DESCRIPTION (provided by applicant): The long-term goal of this project is to elucidate the molecular pathogenesis underlying pediatric high- grade gliomas (HGGs). Glioblastoma is the most common and lethal type of primary brain tumor in humans, which accounts for 52% of all functional tissue brain tumor cases. Despite decades of concerted therapeutic efforts, gliomas remain incurable. The major problem is that the real pathogenesis underlying this disease is essentially unknown. Recent studies have linked pediatric and young adult HGGs with mutations in SETD2 and Gly34Arg/Val (G34R/V) substitutions in histone H3.3, but the molecular mechanism(s) by which the altered SETD2 and H3.3 drive malignancy of pediatric and young adult HGGs are not elucidated. Because SETD2 encodes the only known methyltransferase specific for histone H3 lysine36 trimethylation (H3K36me3), and H3.3G34R/V mutations lead to significant decrease in H3K36me3 levels, these observations have pointed the true culprit of pediatric and young adult HGGs to a mechanism that is regulated by H3K36me3. Strikingly, we have recently shown that H3K36me3 is essential for a critical genome-maintenance system called DNA mismatch repair (MMR) by recruiting mismatch recognition protein hMutSα to chromatin through its direct interaction with hMutSα, and that cells depleted of SETD2/H3K36me3 display a mutator phenotype usually seen in cells defective in MMR genes. We therefore hypothesize that abnormal SETD2 and H3.3 promote pediatric and young adult HGG tumorigenesis by inactivating the MMR function via blocking H3K36 trimethylation. To test this hypothesis, two specific aims are proposed in this application. Specific Aim 1 is to directly determine H3K36me3 levels and mutator phenotype in pediatric HGGs with SETD2 or H3.3G34R/V mutations. Specific Aim 2 is to measure genomic instability and the dynamic interaction between H3K36me3 and hMutSα in glioma cell lines expressing G34R/V H3.3. A successful completion of the proposed study will reveal the real pathogenesis of pediatric HGGs, providing a novel biomarker for cancer detection. More importantly, since tumor cells defective in MMR are highly resistant to many chemotherapeutic drugs including temozolomide, which is widely used for and causes resistance in glioma therapy, this study will also offer new strategies to improve glioma therapy.

描述（由申请人提供）：该项目的长期目标是阐明儿童高级别胶质瘤（HGG）的分子发病机制。胶质母细胞瘤是人类最常见和致命的原发性脑肿瘤，占所有功能组织脑肿瘤病例的52%。尽管经过几十年的共同努力，神经胶质瘤仍然无法治愈。主要的问题是，这种疾病的真实的发病机制基本上是未知的。最近的研究已经将儿童和年轻成人HGG与组蛋白H3.3中的SETD 2和Gly 34 Arg/瓦尔（G34 R/V）取代中的突变联系起来，但是改变的SETD 2和H3.3驱动儿童和年轻成人HGG的恶性肿瘤的分子机制尚未阐明。由于SETD 2编码唯一已知的特异于组蛋白H3赖氨酸36三甲基化（H3 K36 me 3）的甲基转移酶，并且H3.3G34R/V突变导致H3 K36 me 3水平显著降低，因此这些观察结果将儿童和年轻成人HGG的真正罪魁祸首指向由H3 K36 me 3调节的机制。引人注目的是，我们最近发现H3 K36 me 3对于一个称为DNA错配修复（MMR）的关键基因组维持系统至关重要，通过与hMutSα的直接相互作用将错配识别蛋白hMutSα招募到染色质中，并且缺失SETD 2/H3 K36 me 3的细胞显示出MMR基因缺陷细胞中常见的突变表型。因此，我们假设异常的SETD 2和H3.3通过阻断H3 K36三甲基化使MMR功能失活而促进儿童和年轻成人HGG肿瘤发生。为了检验这一假设，在本申请中提出了两个具体目标。具体目标1是直接确定具有SETD 2或H3.3G34R/V突变的儿科HGG中的H3 K36 me 3水平和增变子表型。具体目标2是测量表达G34 R/V H3.3的胶质瘤细胞系中H3 K36 me 3和hMutSα之间的基因组不稳定性和动态相互作用。该研究的成功完成将揭示儿童HGG的真实的发病机制，为癌症检测提供新的生物标志物。更重要的是，由于MMR缺陷的肿瘤细胞对包括替莫唑胺在内的许多化疗药物具有高度耐药性，替莫唑胺广泛用于胶质瘤治疗并导致耐药性，因此这项研究也将为改善胶质瘤治疗提供新的策略。