Targeting oncogene expression to endothelial cells induces proliferation of the myelo-erythroid lineage by repressing the notch pathway
Targeting oncogene expression to endothelial cells induces proliferation of the myelo-erythroid lineage by repressing the notch pathway
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DOI：
10.1038/leu.2013.132
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发表时间：
2013-11-01
期刊：
影响因子：
11.4
通讯作者：
Mione, M. C.
中科院分区：
文献类型：
--
作者：
Alghisi, E.;Distel, M.;Mione, M. C.
参与血液系统恶性肿瘤发展的人类癌基因已被广泛用于建立实验性白血病模型。然而，由于遗传复杂性或难以靶向白血病起始细胞，髓性白血病模型很少完全再现人类疾病。在这里，我们使用斑马鱼的遗传模型，以诱导表达的致癌RAS的内皮细胞，包括生血内皮的背主动脉生成造血细胞，并观察到的发展骨髓-红细胞增殖性疾病。在幼虫中，该表型的特征在于血管系统的破坏和尾部造血组织的显著扩张。在少数存活的青少年中，肾骨髓中未成熟造血细胞数量增加，髓系成熟停滞。外周血显示成红细胞和髓系祖细胞增加。我们发现异常表型与Notch途径的下调相关，而过表达活化形式的Notch与癌基因一起阻止了骨髓红细胞隔室的扩增。这项研究确定了造血内皮细胞中致癌事件后Notch通路的下调是骨髓-红细胞疾病发病机制中的重要步骤，并描述了这种转化的一些潜在效应物。
Human oncogenes involved in the development of hematological malignancies have been widely used to model experimental leukemia. However, models of myeloid leukemia rarely reproduce the human disease in full, due to genetic complexity or to difficulties in targeting leukemia initiating cells. Here, we used a zebrafish genetic model to induce the expression of oncogenic RAS in endothelial cells, including the hemogenic endothelium of the dorsal aorta that generates hematopoietic cells, and observed the development of a myelo-erythroid proliferative disorder. In larvae, the phenotype is characterized by disruption of the vascular system and prominent expansion of the caudal hematopoietic tissue. In few surviving juveniles, increased number of immature hematopoietic cells and arrest of myeloid maturation was found in kidney marrow. Peripheral blood showed increased erythroblasts and myeloid progenitors. We found that the abnormal phenotype is associated with a downregulation of the Notch pathway, whereas overexpressing an activated form of Notch together with the oncogene prevents the expansion of the myeloerythroid compartment. This study identifies the downregulation of the Notch pathway following an oncogenic event in the hemogenic endothelium as an important step in the pathogenesis of myelo-erythroid disorders and describes a number of potential effectors of this transformation.