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Animal Models

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

Leukemia volume 27, pages 2229–2241 (2013)Cite this article

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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.

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Acknowledgements

We are grateful to D Traver, K Kawakami, R Koester, M Tada, M Affolter, N Lawson, G Lieschke, L Zon and member of his lab, for plasmids, transgenic lines and suggestions in the course of this project. ZF Screen for carrying out the deep sequencing. EA was supported by a COST-STSM-BM0804-040712-019714 travel fellowship; MD by a postdoctoral fellowship of the German Academic Exchange Service (DAAD) and an EMBO fellowship. EA, MM and DR were partially supported by BCC Pompiano e Franciacorta and Lions Bassa Bresciana Foundation. MCM was supported by the Helmholtz research programme BioInterfaces.

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Authors and Affiliations

  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

    E Alghisi, M Malagola & D Russo

  2. Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany

    E Alghisi & M C Mione

  3. UCSD, Cellular and Molecular Medicine, La Jolla, CA, USA

    M Distel

  4. Departments of Surgery and Medicine, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY, USA

    V Anelli

  5. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA

    C Santoriello

  6. Biozentrum der Universität Basel, Basel, Switzerland

    L Herwig & A Krudewig

  7. ZF-screens BV, Leiden, The Netherlands

    C V Henkel

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  1. E Alghisi
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Corresponding author

Correspondence to M C Mione.

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Author contributions

E Alghisi and MC Mione conceived the study, carried out most of the experimental work and analysis, and wrote the paper. M Distel carried out the experiments shown in Figure 4, in the supplementary movies and in Supplementary Figure S3, provided interpretation and analysis of the data and contributed to writing the manuscript. M Malagola contributed to cytological analysis and to the writing of the Introduction. V Anelli and C Santoriello contributed to the experiments shown in Figures 2, 6 and 7. L Herwig and A Krudewig generated the transgenic line tg(fli1ep:GAL4FF)ubs3, C Henkel performed the analysis of the deep sequencing results and contributed to Figure 7d. Russo provided insights into the interpretation of the data. All authors commented on the ms.

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Alghisi, E., Distel, M., Malagola, M. et al. Targeting oncogene expression to endothelial cells induces proliferation of the myelo-erythroid lineage by repressing the notch pathway. Leukemia 27, 2229–2241 (2013). https://doi.org/10.1038/leu.2013.132

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