少突胶质细胞瘤是一类较少见的颅内原发性恶性肿瘤,其中50-70%含有1p/19q染色体的杂合性缺失。近年研究表明此染色体的异常源于t(1;19)(q10;p10)的不平衡易位。该染色体缺失与病人对化疗的敏感性和化疗后的不复发生存时间延长呈明显正相关，但产生其有利效果的原因尚不清楚。模拟少突胶质细胞瘤1p/19q 全染色体臂的缺失建立细胞模型是一种理想的研究其保护机制和进行药物筛选的手段。但因其技术性挑战较大，目前世界上尚没有具备1p/19q染色体杂合性缺失特征的胶质细胞瘤的等基因细胞系。本研究将通过rAAV基因靶向技术与Cre/loxP系统诱导建立一系列有(1;19)(q10;p10)染色体易位的胶质细胞瘤细胞系。然后用FISH,CGH,cDNA 微阵列等方法验证所创建的模型的正确性。最后，用一个初步的合成致死药物筛选发现1p/19q染色体杂合性缺失胶质瘤细胞的抑制物以证实此模型的可用性。

Oligodendrogliomas are rare primary malignant brain tumors, and 50-70% of these tumors harbor a 1p/19q chromosomal deletion. Recent studies suggest this aberration arises from an imbalanced reciprocal translocation, t(1;19)(q10;p10). Patients with this co-deletion respond better to chemotherapy and/or radiotherapy and have longer recurrence free survival, but the mechanism remains unknown. The development of isogenic cell lines for this disease will prove a critical tool for elucidating the mechanism(s). However, construction of such cell lines has been technically challenging, in part because it is difficult to model the 1p/19q whole-chromosome arm losses. In this application, we propose to create a panel of glioma cell lines with a Cre/loxP-inducible (1;19)(q10;p10) translocation. LoxP sites with flanking antibiotic and fluorescent protein selection genes will be inserted into the 1p and 19q chromosome arms using established recombinant Adeno-Associated Virus (rAAV) gene targeting techniques. Then，these inducible cell lines will be characterized sequentially by fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH) and cDNA microarray gene profiling studies, in order to confirm that they accurately model the 1p/19q co-deletion seen in primary oligodendroglioma tumors. Finally, we will validate our novel inducible cell lines in a pilot synthetic lethal drug screen for inhibitors of 1p/19q co-deleted glioma cells.