ZFIN ID: ZDB-PUB-130604-12
Targeting oncogene expression to endothelial cells induces proliferation of the myelo-erythroid lineage by repressing the notch pathway
Alghisi, E., Distel, M., Malagola, M., Anelli, V., Santoriello, C., Herwig, L., Krudewig, A., Henkel, C.V., Russo, D., and Mione, M.C.
Date: 2013
Source: Leukemia   24(6): 943-53 (Journal)
Registered Authors: Anelli, Viviana, Distel, Martin, Mione, Marina, Santoriello, Cristina
Keywords: none
Microarrays: GEO:GSE41988
MeSH Terms:
  • Animals
  • Apoptosis
  • Blotting, Western
  • Cell Differentiation
  • Cell Lineage*
  • Cell Proliferation*
  • Cell Transformation, Neoplastic/pathology*
  • Endothelium, Vascular/metabolism
  • Endothelium, Vascular/pathology*
  • Erythroid Precursor Cells/metabolism
  • Erythroid Precursor Cells/pathology*
  • Fluorescent Antibody Technique
  • Hematopoiesis
  • Humans
  • Myeloid Cells/metabolism
  • Myeloid Cells/pathology*
  • Proto-Oncogene Protein c-fli-1
  • Proto-Oncogene Proteins/genetics*
  • Proto-Oncogene Proteins/metabolism
  • RNA, Messenger/genetics
  • Real-Time Polymerase Chain Reaction
  • Receptor, Notch1/genetics
  • Receptor, Notch1/metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • ras Proteins/genetics*
  • ras Proteins/metabolism
PubMed: 23625115 Full text @ Leukemia

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 myelo-erythroid 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.