Role of Methyltransferases in MYC-driven Medulloblastoma

甲基转移酶在 MYC 驱动的髓母细胞瘤中的作用

基本信息

批准号：
10270673
负责人：
MARTINE F. ROUSSEL (SHERR)
金额：
$ 45.06万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10270673
关键词：
ATAC-seq Address Affect Age Allografting Automobile Driving Binding Proteins Blood - brain barrier anatomy Brain Brain Neoplasms Cell Line Cell model ChIP-seq Child Chromatin Chromatin Remodeling Factor Chromatin Structure Clinical Trials Complex Data Dependence Development Disease Dropout EZH2 gene Enzymes Epigenetic Process FDA approved Funding Future Gene Expression Genes Goals Grant Histones Human In Vitro Incidence Knockout Mice Lead Libraries Luciferases Lysine Maintenance Malignant - descriptor Malignant Childhood Neoplasm Malignant neoplasm of brain Mass Spectrum Analysis Methylation Methyltransferase Modification Molecular Mus Mutation Neoplasm Metastasis Neoplasms Nuclear Oncogenes Operative Surgical Procedures Pathway interactions Patients Pattern Pediatric Neoplasm Pharmaceutical Preparations Pharmacology Post-Translational Protein Processing Prognosis Proteins Proteome Proteomics Radiation Recurrence Repressor Proteins Role SHH gene SMYD3 gene Shapes Subgroup Systems Biology Testing Therapeutic Therapeutic Intervention Transgenic Mice Tumor Suppressor Proteins Work Xenograft procedure base chemotherapy combinatorial epigenetic regulation expectation experience functional loss gain of function genome-wide hindbrain histone methyltransferase improved in vivo inhibitor/antagonist medulloblastoma mouse model new therapeutic target novel novel therapeutics overexpression programs small hairpin RNA success therapeutic target transcriptome transcriptomics treatment effect tumor tumorigenesis

项目摘要

Project Summary/Abstract Medulloblastoma (MB) is a tumor of the hindbrain that occurs in children with a peak incidence between the ages of 3 and 7. Based on extensive molecular evidence, medulloblastoma is classified into four major groups, among which Group (G3) MB with MYC overexpression, carry the worse prognosis. Thus, novel therapies are needed to effectively treat these aggressive brain tumors in children. Recent genome wide sequencing and 850K methylation profiling showed that G3MB has a paucity of mutations, most of which occur in epigenetic regulatory enzymes that modify histones. However, a significant proportion of MYC-driven G3 MBs do not harbor any mutations suggesting that additional non-mutated epigenetic regulators, so called “hidden drivers”, might act as oncogenes or tumor-suppressors, implicated in shaping the chromatin structure and driving G3 MB genesis. We performed a dropout shRNA screen of 243 unique mouse epigenetic regulators, and the top hit was SMYD3, a H4K5me1 methyltransferase that importantly regulates MYC expression. Systems biology reveals that SMYD3 is most overexpressed in G3 MBs that specifically overexpress MYC (type II) compared to the other G3 MB subtypes and MB Groups. To address the role of SMYD3 in driving G3 MB, we will use multiple complementary approaches in vitro and in vivo in both mouse and human G3MB to 1) assess how SMYD3 overexpression contributes to G3MB tumorigenesis, 2) use mass spectrometry to identify interacting proteins and define the role of SMYD3 in shaping the transcriptome, proteome and phosphoproteome, and 3) evaluate whether SMYD3 and other epigenetic regulators could be considered as therapeutic targets for future clinical trials in MYC-driven G3MB. Our ultimate goal is to identify epigenetic vulnerabilities that can be therapeutically targeted to treat the most aggressive forms of the disease.

项目摘要/摘要髓母细胞瘤（MB）是后脑的肿瘤，发生在年龄段的儿童中在3和7中，基于广泛的分子证据，髓母细胞瘤分为四个主要组，哪组（G3）MB具有MYC过表达，具有较差的预后。那是需要新颖的疗法有效治疗儿童中这些侵略性脑肿瘤。最近的基因组广泛测序和850K 甲基化分析表明，G3MB的突变很少，其中大部分发生在表观遗传调节中修饰组蛋白的酶。但是，很大一部分由MYC驱动的G3 MB都没有任何突变表明其他未突出的表观遗传调节剂，所谓的“隐藏驱动因素”，可能是肿瘤基因或肿瘤抑制剂，暗示着塑造染色质结构并驱动G3 MB创世纪。我们执行了243个独特的小鼠表观遗传调节剂的辍学shRNA屏幕，最高命中率是Smyd3，一个 H4K5ME1甲基转移酶，重要地调节MYC表达。系统生物学揭示了Smyd3 与其他G3 MB相比，G3 MB中最过表达的G3 MB（II型）亚型和MB组。为了解决SMYD3在驾驶G3 MB中的作用，我们将使用多个完整性在小鼠和人G3MB中的体外和体内接近1）评估Smyd3过表达的评估有助于G3MB肿瘤发生，2）使用质谱法来识别相互作用的蛋白质并定义角色 Smyd3在塑造转录组，蛋白质组和磷蛋白蛋白质组中的作用，以及3）评估SMYD3和SMYD3和是否是否其他表观遗传调节剂可以视为MYC驱动的将来临床试验的治疗靶标 G3MB。我们的最终目标是确定可以热针对治疗的表观遗传漏洞最激进的疾病形式。