title: Targeting oncogene expression to endothelial cells induces proliferation of the myelo-erythroid lineage by repressing the Notch pathway.
abstract: 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.
authors.affiliation: 1] Chair of Hematology and Unit of Blood Disease and Stem Cell Transplantation Department of Clinical and Experimental Sciences, University of Brescia Medical School, Brescia, Italy [2] Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Alghisi
authors.forename: M
authors.initials: M
authors.lastname: Distel
authors.forename: M
authors.initials: M
authors.lastname: Malagola
authors.forename: V
authors.initials: V
authors.lastname: Anelli
authors.forename: C
authors.initials: C
authors.lastname: Santoriello
authors.forename: L
authors.initials: L
authors.lastname: Herwig
authors.forename: A
authors.initials: A
authors.lastname: Krudewig
authors.forename: C V
authors.initials: CV
authors.lastname: Henkel
authors.forename: D
authors.initials: D
authors.lastname: Russo
authors.forename: M C
authors.initials: MC
authors.lastname: Mione
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D015672:Erythroid Precursor Cells / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D006410:Hematopoiesis; D006801:Humans; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C078433:FLI1 protein, human; C117307:KRAS protein, human; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins