Targeting oncogene expression to endothelial cells induces proliferation of the myelo-erythroid lineage by repressing the Notch pathway.

Leukemia. 2013 Nov;27(11):2229-41. Epub 2013 Apr 29

E Alghisi ¹ , M Distel , M Malagola , V Anelli , C Santoriello ,

E Alghisi ¹ , M Distel , M Malagola , V Anelli , C Santoriello , L Herwig , A Krudewig , C V Henkel , D Russo , M C Mione

+ et al

Author information

¹ 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.

摘要

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.

基因

trim35-35, mrc1a, si:ch211-286f9.2, spi1b, her6, lmo2, gata1a, myb, lcp1, tal1, gpr182, mpx, nr0b2a, dab2, mmp9, mpl, h2afy2, lyve1b, stab2, parvab, vsg1, notch3, runx1, notch1b, NOTCH1

原始数据

保存测序数据

Sample name	Organism	Experiment title	Sample type	Library instrument	Attributes
Sample name	Organism	Experiment title	Sample type	Library instrument	Stage	genetic background	genotype	source name	tissue
Fli NICD 3df	Danio rerio	GSM1029656: Fli NICD 3df; Danio rerio; RNA-Seq	RNA-Seq	Illumina HiSeq 2000	3 days post fertilization	AB	(Tg(fli1ep:GAL4FF)ubs3; tg(UAS:NICD)kca3	Whole zebrafish larvae	whole larvae
FliRas 3df	Danio rerio	GSM1029655: FliRas 3df; Danio rerio; RNA-Seq	RNA-Seq	Illumina HiSeq 2000	3 days post fertilization	AB	(Tg(fli1ep:GAL4FF)ubs3; Tg(UAS:eGFP-HRASV12)io006	Whole zebrafish larvae	whole larvae
CTRL 3dpf	Danio rerio	GSM1029654: CTRL 3dpf; Danio rerio; RNA-Seq	RNA-Seq	Illumina HiSeq 2000	3 days post fertilization	AB	wild type	Whole zebrafish larvae	whole larvae