新融合基因NUP98-HOXD8的致白血病机制研究

Rearrangements of 11p15 involving NUP98 gene are common chromosomal abnormalities in hematologic malignancies including de novo and therapy-related acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndromes（MDS）, and advanced stages of chronic myeloid leukemia (CML). The NUP98 gene locates at 11p15 and encodes the nup98 (nucleoporin 98 kDa) protein, a mobile component of the nuclear pore, which involved in nucleocytoplasmic trafficking and transcriptionally active of chromatin. The partner genes of NUP98 is diverse, located at many chromosomes, among which homeobox genes are identified as the most common and important partners, such as NUP98-HOXA9, NUP98-HOXC13, and NUP98-HOXD11. Recently,we sucessfully cloned a novel fuse gene NUP98-HOXD8, which has never been reported. In addition, as an important homebox gene,the biological and characteristics of HOXD8 in hematologic malignancies remains unclear. We plan to determine the role of NUP98-HOXD8 fusion gene in leukemogenesis using multiple in vivo and in vitro techniques, such as gene expression microarray, gene transfection, RNA interference, and animal models. This study will provide more details on the pathogenesis of NUP98 fusion gene and hox genes in leukemia.

11p15重排是恶性血液病中常见的一种染色体易位，可见于急性髓细胞白血病、急性淋巴细胞白血病、慢性髓细胞白血病急变及骨髓增生异常综合征中。受累基因为NUP98，该基因编码蛋白为核孔蛋白复合体的重要组成部分，其对手基因多变，分布于各条染色体，以同源盒（HOX）家族基因最为常见，如NUP98-HOXA9、NUP98-HOXC13和NUP98-HOXD11等。申请人前期筛选到了150例伴有NUP98重排的病例，并成功克隆了一个新的白血病融合基因NUP98-HOXD8。目前NUP98-HOXD8的致白血病机制尚不明确，作为在造血调控中有重要作用同源盒基因家族成员之一，HOXD8基因在血液病中的功能仍不清楚。本课题拟在前期工作基础上采用基因转染、RNA干扰和小鼠动物模型等手段，从体内外两方面研究NUP98-HOXD8的生物学功能和致病白血病机制，为阐明NUP98融合蛋白的致病机制提供理论和实验依据。

11p15重排是恶性血液病中常见的一种染色体易位，可见于急性髓细胞白血病、急性淋巴细胞白血病、慢性髓细胞白血病急变及骨髓增生异常综合征中。受累基因为NUP98，该基因编码蛋白为核孔蛋白复合体的重要组成部分，其对手基因多变，分布于各条染色体，以同源盒（HOX）家族基因最为常见，如NUP98-HOXA9、NUP98-HOXC13和NUP98-HOXD11等。申请人前期筛选到了150例伴有NUP98重排的病例，并成功克隆了一个新的白血病融合基因NUP98-HOXD8。RNA-SEQ结果显示NUP98-HOXD8是一个再现性的融合基因，主要出现在MDS中。作为在造血调控中有重要作用同源盒基因家族成员之一，HOXD8基因在血液病中的功能仍不清楚。在体外NUP98-HOXD8的功能与NUP98-HOXA9较为相似，但作用相对较弱。本课题在前期工作基础上采用基因转染、RNA干扰和小鼠动物模型等手段，从体内外两方面研究NUP98-HOXD8的生物学功能和致病白血病机制，为阐明NUP98融合蛋白的致病机制提供理论和实验依据。