PAX3/FKHR IN ALVEOLAR RHABDOMYOSARCOMA

肺泡型横纹肌肉瘤中的 PAX3/FKHR

• 批准号: 6595013
• 负责人: GERARD C GROSVELD
• 金额: $ 24.14万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6595013
• 关键词: complementary DNA; gene induction /repression; genetically modified animals; laboratory mouse; microarray technology; neoplasm /cancer genetics; oncoproteins; posttranslational modifications; protein protein interaction; protein structure function; retinoblastoma protein; rhabdomyosarcoma; tissue /cell culture; transcription factor

Rhabdomyosarcoma (RMS) is the third most common soft tissue sarcoma in children. Alveolar RMS is characterized by the t(2;13) that results in the expression of the activated transcription factor Pax3-FKHR. The long-term goal of this project is to identify the tumorigenic events that result in alveolar RMS. Because Pax3 plays an important role in the embryonic development of muscles, the proposed hypothesis is that disruption of Pax3-regulated gene expression by Pax3-FKHR is crucial for the development of alveolar RMS. However, expression of Pax3- FKHR in mice is insufficient to recapitulate disease. Forced expression of Pax3 and Pax3-FKHR in primary mouse myoblasts increases their rate of proliferation, and Pax3-FKHR, but not Pax3, blocks their differentiation. Therefore, the following specific aims are proposed: Aim 1) The mechanism by which Pax3-FKHR causes the acceleration of the cell cycle in primary myoblasts and the transcriptional targets of Pax3 and Pax3-FKHR in myoblasts will be identified. This aim will be accomplished by analyzing the interactions between Pax3-FKHR and cell-cycle regulators and by performing cDNA microarray analyses of myoblasts. Aim 2) The genes that cooperate with Pax3-FKHR in transforming primary myogenic in vitro and in vivo will be identified. Complementary mutagenesis approaches will be used to identify the additional genetic changes that are essential for tumorigenic transformation. Such changes will be introduced into mouse models to test their ability to cooperate with Pax3-FKHR in tumorigenesis. The relevance of such changes in human alveolar RMS will be determined by testing for disease-specific changes in expression of these genes in human RMS cell lines and tumors. Together, these studies will provide valuable insights into the disruption of molecular pathways that cause alveolar RMS in children. This understanding may ultimately result in the identification of new targets that will lead to improved therapies for this disease.

横纹肌肉瘤（RMS）是儿童第三常见的软组织肉瘤。肺泡RMS的特征在于t（2;13），其导致活化的转录因子Pax 3-FKHR的表达。本项目的长期目标是确定导致肺泡RMS的致瘤性事件。由于Pax 3在肌肉的胚胎发育中起着重要作用，因此提出的假设是Pax 3-FKHR对Pax 3调节的基因表达的破坏对肺泡RMS的发育至关重要。然而，Pax 3- FKHR在小鼠中的表达不足以概括疾病。在原代小鼠成肌细胞中Pax 3和Pax 3-FKHR的强制表达增加了它们的增殖速率，并且Pax 3-FKHR而不是Pax 3阻断了它们的分化。因此，本研究提出以下具体目标：1）目的：明确Pax 3-FKHR促进原代成肌细胞细胞周期的机制，以及Pax 3和Pax 3-FKHR在成肌细胞中的转录靶点。这一目标将通过分析Pax 3-FKHR和细胞周期调节因子之间的相互作用以及通过对成肌细胞进行cDNA微阵列分析来实现。目的2）筛选与Pax 3-FKHR协同转化原代肌源性细胞的基因。互补诱变方法将用于鉴定致瘤转化所必需的其他遗传变化。这些变化将被引入小鼠模型中，以测试它们在肿瘤发生中与Pax 3-FKHR合作的能力。通过检测这些基因在人RMS细胞系和肿瘤中表达的疾病特异性变化，将确定人肺泡RMS中这些变化的相关性。总之，这些研究将提供有价值的见解破坏分子途径，导致肺泡RMS的儿童。这种理解可能最终导致识别新的靶点，从而改善这种疾病的治疗方法。