白血病新融合基因PAX5-UBE2D4的致病机制研究

PAX5 encodes an important transcription factor involved in the development of B cell lineage. Genetic abnormalities involving PAX5 gene, such as fusion with other genes, deletions, and mutations, have been detected in about 34% of adult and 30% of pediatric precursor B-cell acute lymphoblastic leukemia. However, the role of PAX5 fusion proteins in leukemogenesis remain largely unknown.In this study, we identified 7 patients with leukemia harboring dic(7;9)(p11-13;p13) rearrangements by screening patients with leukemia. Moreover, we identified a novel fusion gene involving PAX5 gene in a patients with precursor B-ALL, which results in an in-frame fusion of PAX5 to ubiquitin-conjugating enzyme E2D4 (UBE2D4). We plan to identify other fusion genes involving the PAX5 gene and determine the role of PAX5-UBE2D4 and other fusion proteins in leukemogenesis using multiple in vivo and in vitro techniques, such as gene expression microarray, array-based comparative genomic hybridization, gene transfection, RNA interference, and animal models. This study will provide more details on the pathogenesis of PAX5 fusion protein in leukemia.

PAX5是参与调控B淋巴细胞发育的重要转录因子，累及PAX5基因的遗传学异常是急性B淋巴细胞白血病（B-ALL）最常见的分子遗传学异常之一。约34%的成人和30%的儿童B-ALL患者伴有PAX5基因的缺失、突变和染色体易位，但PAX5基因异常的致白血病机制尚未完全明确。申请人在前期工作中,筛选到7例伴有dic(7;9)(p11-13;p13)易位的白血病患者，并对其断裂点进行精确定位，克隆了一个新的累及PAX5基因和泛素结合酶UBE2D4的融合基因，PAX5-UBE2D4。本课题拟采用基因表达谱芯片、array-CGH、基因转染、RNA干扰和小鼠移植模型等手段，进一步克隆PAX5的新对手基因，并从体内外两方面揭示PAX5-UBE2D4等融合蛋白及其协同遗传学异常的致病分子机理和靶向调控途径。本课题将为阐明PAX5融合蛋白的致白血病机制、寻找新的治疗靶点、实现个体化的治疗提供理论和实验依据。

PAX5 是参与调控 B 淋巴细胞发育的重要转录因子，累及 PAX5 基因的遗传学异常是急性 B 淋巴细胞白血病（B-ALL）最常见的分子遗传学异常之一。约 34%的成人和 30%的儿童 B-ALL 患者伴有 PAX5 基因的缺失、突变和染色体易位，但 PAX5 基因异常的致白血病机制尚未完全明确。通过本项目研究工作，我们从1200余例急性白血病患者中筛选到 7 例伴有 dic(7;9)(p11-13;p13)易位的白血病患者，并对其断裂点进行精确定位，克隆了一个新的累及 PAX5 基因和泛素结合酶 UBE2D4的融合基因， PAX5-UBE2D4。采用基因表达谱芯片、 array-CGH、基因转染、 RNA 干扰和裸鼠成瘤等手段，进一步克隆 PAX5 的新对手基因，并从体内外两方面揭示PAX5-UBE2D4 融合蛋白及PAX5在Ph阳性急性淋巴细胞白血病种的作用，初步探讨了其致病分子机理和靶向调控途径。本课题将为阐明 PAX5 融合蛋白的致白血病机制、寻找新的治疗靶点、治疗Ph阳性急性淋巴细胞白血病以及实现个体化的治疗提供理论和实验依据。