期刊
LEUKEMIA
卷 27, 期 11, 页码 2229-2241出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2013.132
关键词
myeloid leukemia model; hemogenic endothelium; RAS; myelo-erythroid proliferative neoplasm; zebrafish
资金
- German Academic Exchange Service (DAAD)
- EMBO fellowship
- BCC Pompiano e Franciacorta and Lions Bassa Bresciana Foundation
- Helmholtz research programme BioInterfaces
- [COST-STSM-BM0804-040712-019714]
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.
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