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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Directing oncogenic fusion genes into stem cells via an SCL enhancer.
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Directing oncogenic fusion genes into stem cells via an SCL enhancer.

机译：通过SCL增强子将致癌融合基因导入干细胞。

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摘要

TEL-TRKC is a fusion gene generated by chromosomal translocation and encodes an activated tyrosine kinase. Uniquely, it is found in both solid tumors and leukemia. However, a single exon difference (in TEL) in TEL-TRKC fusions is associated with the two sets of cancer phenotypes. We expressed the two TEL-TRKC variants in vivo by using the 3' regulatory element of SCL that is selectively active in a subset of mesodermal cell lineages, including endothelial and hematopoietic stem cells and progenitors. The leukemia form of TEL-TRKC (-exon 5 of TEL) enhanced hematopoietic stem cell renewal and initiated leukemia. In contrast, the TEL-TRKC solid tumor variant (+ TEL exon 5) elicited an embryonic lethal phenotype with impairment of both angiogenesis and hematopoiesis indicative of an effect at the level of the hemangioblasts. The ability of TEL-TRKC to repress expression of Flk1, a critical regulator of early endothelial and hematopoietic cells, depended on TEL exon 5. These data indicate that related oncogenic fusion proteins similarly expressed in a hierarchy of early stem cells can have selective, cell type-specific developmental impacts.
机译：TEL-TRKC是由染色体易位产生的融合基因，编码一个激活的酪氨酸激酶。独特地，它在实体瘤和白血病中都发现。但是，TEL-TRKC融合中的单个外显子差异（在TEL中）与两组癌症表型有关。我们通过使用SCL的3'调控元件在体内表达了两个TEL-TRKC变体，该元件在中胚层细胞谱系的子集（包括内皮细胞和造血干细胞以及祖细胞）中具有选择性活性。 TEL-TRKC的白血病形式（TEL的第5外显子）增强造血干细胞更新并引发白血病。相反，TEL-TRKC实体瘤变体（+ TEL外显子5）引起胚胎致死表型，血管生成和造血功能均受损，这表明在成血成血管细胞水平上有作用。 TEL-TRKC抑制Flk1（早期内皮细胞和造血细胞的关键调节因子）表达的能力取决于TEL外显子5。这些数据表明，类似表达于早期干细胞中的相关致癌融合蛋白可以具有选择性类型特定的发展影响。

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