The common viral insertion site Evi12 is located in the 5′-noncoding region of Gnn, a novel gene with enhanced expression in two subclasses of human acute myeloid leukemia
The common viral insertion site Evi12 is located in the 5′-noncoding region of Gnn, a novel gene with enhanced expression in two subclasses of human acute myeloid leukemia
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DOI：
10.1128/jvi.79.9.5249-5258.2005
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发表时间：
2005-05-01
影响因子：
5.4
通讯作者：
Delwel, R
中科院分区：
文献类型：
--
作者：
van den Akker, E;Vankan-Berkhoudt, Y;Delwel, R
白血病和淋巴瘤疾病位点Evi 12被定位到一个新基因的非编码区，Gnn（命名为Grp 94相邻核苷酸酶），该基因位于小鼠10号染色体上Grp 94/Tra 1基因的上游。Gnn基因在小鼠和人类中是保守的。在HEK-293细胞中表达GFP和Gnn cDNA异构体之间的融合构建体表明，Gnn蛋白主要位于细胞质中。免疫印迹实验表明，在大多数器官中存在多种Gnn蛋白亚型，在骨髓和脾脏中检测到的蛋白质表达水平最低。含有Evi 12的白血病细胞系NFS 107显示出类似于150 kDa Gnn同种型（Gnn 107）的高水平表达，而在对照细胞系中未观察到。过表达可能是由于病毒插入Evi 12。Gnn（107）蛋白可能由Gnn cDNA同种型编码，该同种型仅在NFS 107细胞中表达，并包括TU 12 B1-TY序列，TU 12 B1-TY是一种与5 '-核苷酸酶具有同源性的推定蛋白。有趣的是，使用285名急性髓性白血病（AML）患者的AffyIdea基因表达数据，我们发现GNN/TU 12 B1-TY表达在两个AML簇中特异性增加。一个簇由所有具有t（8;21）易位的AML患者组成，第二个簇由具有携带FLT 3内部串联重复的正常核型的AML患者组成。这些发现表明，我们发现了一种新的原癌基因，可能与某些类型的人类白血病有因果关系。
The leukemia and lymphoma disease locus Evi12 was mapped to the noncoding region of a novel gene, Gnn (named for Grp94 neighboring nucleotidase), that is located immediately upstream of the Grp94/Tra1 gene on mouse chromosome 10. The Gnn gene is conserved in mice and humans. Expression of fusion constructs between GFP and Gnn cDNA isoforms in HEK-293 cells showed that Gnn proteins are located mainly in the cytoplasm. Immunoblotting experiments demonstrated the presence of multiple Gnn protein isoforms in most organs, with the lowest levels of expression of the protein detected in bone marrow and spleen. The Evi12-containing leukemia cell line NFS107 showed high levels of expression of a similar to 150-kDa Gnn isoform (Gnn 107) that was not observed in control cell lines. Overexpression may be due to the viral insertion in Evi12. The Gnn(107) protein is probably encoded by a Gnn cDNA isoform that is expressed exclusively in NFS107 cells and that includes sequences of TU12B1-TY, a putative protein with homology to 5'-nucleotidase enzymes. Interestingly, using Affymetrix gene expression data of a cohort of 285 patients with acute myeloid leukemia (AML), we found that GNN/TU12B1-TY expression was specifically increased in two AML clusters. One cluster consisted of all AML patients with a t(8;21) translocation, and the second cluster consisted of AML patients with a normal karyotype carrying a FLT3 internal tandem duplication. These findings suggest that we identified a novel proto-oncogene that may be causally linked to certain types of human leukemia.