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: 8814446
• 负责人: Guo-Min Li
• 金额: $ 21.22万
• 依托单位: UNIVERSITY OF KENTUCKY
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8814446
• 关键词: Accounting; Biological Assay; Biological Markers; Brain Neoplasms; Cancer Detection; Cell Line; Cells; Childhood; Chromatin; Co-Immunoprecipitations; DNA; DNA Sequence; Detection; Disease; Exhibits; Genes; Genome; Genomic Instability; Gerda brand of difluprednate; Glioblastoma; Glioma; Goals; 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; Research; Resistance; System; Testing; Therapeutic; Tissues; Tumor Cell Line; genome sequencing; glioma cell line; improved; in vivo; neoplastic cell; novel; outcome forecast; public health relevance; research study; temozolomide; tumorigenesis; 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 hMutS? to chromatin through its direct interaction with hMutS?, 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 hMutS? 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最致命的原发性脑肿瘤类型，占所有功能组织脑肿瘤病例的 52%。尽管经过数十年的一致治疗努力，神经胶质瘤仍然无法治愈。主要问题是这种疾病的真正发病机制基本上是未知的。最近的研究已将儿科和年轻成人 HGG 与组蛋白 H3.3 中 SETD2 和 Gly34Arg/Val (G34R/V) 取代的突变联系起来，但 SETD2 和 H3.3 改变驱动儿科和青少年恶性肿瘤的分子机制年轻成人 HGG 尚未阐明。由于 SETD2 编码唯一已知的对组蛋白 H3 赖氨酸 36 三甲基化 (H3K36me3) 具有特异性的甲基转移酶，并且 H3.3G34R/V 突变导致 H3K36me3 水平显着降低，因此这些观察结果指出儿童和年轻成人 HGG 的真正罪魁祸首是以下机制：受 H3K36me3 调节。引人注目的是，我们最近通过招募错配识别蛋白 hMutS 证明，H3K36me3 对于称为 DNA 错配修复 (MMR) 的关键基因组维护系统至关重要。通过与 hMutS? 的直接相互作用，染色质发生突变，并且 SETD2/H3K36me3 耗尽的细胞显示出通常在 MMR 基因缺陷的细胞中看到的突变表型。因此，我们假设异常的 SETD2 和 H3.3 通过阻断 H3K36 三甲基化来灭活 MMR 功能，从而促进儿童和年轻成人 HGG 肿瘤发生。为了检验这一假设，本申请提出了两个具体目标。具体目标 1 是直接确定具有 SETD2 或 H3.3G34R/V 突变的儿科 HGG 中的 H3K36me3 水平和突变表型。具体目标 2 是测量基因组不稳定性以及 H3K36me3 和 hMutS 之间的动态相互作用？在表达 G34R/V H3.3 的神经胶质瘤细胞系中。该研究的成功完成将揭示儿科 HGG 的真正发病机制，为癌症检测提供一种新型生物标志物。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高度耐药，替莫唑胺广泛用于神经胶质瘤治疗并导致耐药性，因此这项研究也将为改善神经胶质瘤治疗提供新策略。