Gene targets of OLIG2 in malignant glioma stem cells

恶性胶质瘤干细胞中 OLIG2 的基因靶点

• 批准号: 7323849
• 负责人: Charles D Stiles
• 金额: $ 42.75万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7323849
• 关键词: Accounting; Address; Attenuated; Biological; Boston; CDKN1A gene; Cell Cycle; Cells; Clinical Protocols; Collection; Complement; Confounding Factors (Epidemiology); Cytotoxic agent; Epidermal Growth Factor Receptor; Gene Targeting; Genes; Genetic; Genetic Transcription; Glioblastoma; Glioma; Growth; Hospitals; Human; Lead; Lesion; Maintenance; Malignant Glioma; Modeling; Mus; Mutate; Operative Surgical Procedures; Radiation; Radiation therapy; Reagent; Resistance; Resolution; Series; Services; Signal Transduction; Stem cells; TP53 gene; Testing; Time; Tumor Stem Cells; Woman; Work; chemotherapy; inhibitor/antagonist; interest; loss of function; malignant phenotype; neuropathology; oncoprotein p21; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; research study; tumor; tumor growth

DESCRIPTION (provided by applicant): The most common form of malignant glioma in humans is termed "primary glioblastoma". These tumors are characterized by amplified/mutated EGFR but are generally wild type with respect to P53 status. The genetic integrity of P53 in primary glioma is at odds with the aggressive growth of these tumors and their notorious resistance to radiation and cytotoxic drugs. In preliminary studies, we have found a potential resolution to this paradox. We show I) that essentially 100% of the CD133 positive stem cells that underlie malignant glioma in humans express the bHLH transcription represser OLIG2, ii) that OLIG2 suppresses expression of P21 - a key cell cycle inhibitor gene that is an inducible target gene of P53 and iii) that OLIG2 is essential for growth in a "genetically relevant" murine model of primary glioma. The objective of our study plan is to test the hypothesis that OLIG2 sustains replication of primary glioma stem cells by opposing the action of P53 and suppressing the expression of P21. This hypothesis makes testable predications that we will address with a series of experiments to be conducted on fresh surgical isolates of malignant glioma. We will complement and validate the work on human tumor stem cells with experiments on murine models of glioma that emulate genetic lesions found in primary glioma and also secondary glioma (wild type EGFR but loss-of-function P53). Specific aims are as follows: Aim 1 is to test the prediction that the expression of P21 is precluded in CD133/OLIG2-positive stem cells of primary (P53 positive) gliomas. Aim 2 is to test the prediction that suppression of OLIG2 will stimulate the expression of P21 in primary glioma stem cells and suppress the malignant phenotype. Aim 3 is to test the prediction that P21 is epistatic to O/_/G2for maintenance of the malignant phenotype in stem cells for primary glioma. Aim 4 is to test the prediction that other P53-inducible genes are also suppressed by OLIG2. These additional OLIG2 targets may account for the notorious resistance of primary gliomas to radiotherapy and chemotherapy. In the fullness of time, the work described may lead to new "drugable targets" for the therapy of malignant glioma in humans.

描述（由申请人提供）：人类恶性胶质瘤最常见的形式被称为“原发性胶质母细胞瘤”。这些肿瘤以EGFR扩增/突变为特征，但就P53状态而言，通常为野生型。原发性胶质瘤中P53的遗传完整性与这些肿瘤的侵袭性生长及其对辐射和细胞毒性药物的臭名昭着的耐药性不一致。在初步研究中，我们已经找到了解决这一悖论的可能方法。我们发现，1)人类恶性胶质瘤中几乎100%的CD133阳性干细胞表达bHLH转录抑制因子OLIG2, 2) OLIG2抑制P21的表达，P21是一种关键的细胞周期抑制基因，是P53的诱导靶基因，3)在“遗传相关”的小鼠原发性胶质瘤模型中，OLIG2对生长至关重要。我们的研究计划的目的是验证OLIG2通过对抗P53的作用和抑制P21的表达来维持原发性胶质瘤干细胞复制的假设。这一假设使可测试的预测，我们将解决一系列的实验进行了新鲜的手术分离恶性胶质瘤。我们将在小鼠胶质瘤模型上进行实验，模拟原发性胶质瘤和继发性胶质瘤（野生型EGFR，但功能丧失的P53）中发现的遗传病变，以补充和验证人类肿瘤干细胞的工作。具体目的如下：目的1验证P21在原发性胶质瘤（P53阳性）CD133/ olig2阳性干细胞中不表达的预测。目的2是验证抑制OLIG2会刺激原发胶质瘤干细胞中P21的表达并抑制恶性表型的预测。目的3是验证P21是否上位于O/_/ g2对原发性胶质瘤干细胞恶性表型维持的预测。目的4是验证其他p53诱导基因也被OLIG2抑制的预测。这些额外的OLIG2靶点可能解释了原发性胶质瘤对放疗和化疗的臭名昭著的耐药性。在适当的时候，所描述的工作可能会导致治疗人类恶性胶质瘤的新的“可药物靶点”。