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The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells

Nature Immunology volume 9, pages 810–819 (2008)Cite this article

Abstract

Ets-related gene (ERG), which encodes a member of the Ets family of transcription factors, is a potent oncogene. Chromosomal rearrangements involving ERG are found in acute myeloid leukemia, acute lymphoblastic leukemia, Ewing's sarcoma and more than half of all prostate cancers; however, the normal physiological function of Erg is unknown. We did a sensitized genetic screen of the mouse for regulators of hematopoietic stem cell function and report here a germline mutation of Erg. We show that Erg is required for definitive hematopoiesis, adult hematopoietic stem cell function and the maintenance of normal peripheral blood platelet numbers.

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Figure 1: Mutation of Erg causes many hematopoietic lineage defects.
Figure 2: The Mld2 mutation disrupts the transcriptional activity of Erg.
Figure 3: The Mld2 mutation results in fewer leukocytes, platelets and spleen colony-forming units.
Figure 4: The Mld2 mutation causes profound defects in the HSC compartment.
Figure 5: LT-HSC and ST-HSC defects in Erg+/Mld2 mice.
Figure 6: Erg is essential for definitive hematopoiesis.
Figure 7: Gene expression in Erg+/Mld2 LSK cells.

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Acknowledgements

We thank J. Corbin and J. Lochland for technical assistance; S. Guzzardi, S. Ross, M. Salzone, C. Evans, P. Pavlidis and K. Trueman for animal husbandry; and D.K. Watson (Medical University of South Carolina) for mice with deletion of the Fli-1 activation domain. Supported by the National Health and Medical Research Council of Australia (grants 461219 and 516726; fellowships to D.J.H., W.S.A. and D.F.H.), the Australian Stem Cell Centre (project 047), the Australian Phenomics Network, the Australian Research Council (B.T.K.), the Australian Department of Education, Science and Training (S.J.L. and C.A.d.G.), the University of Melbourne (E.A.K.), the Cancer Council of Victoria (D.M.) and MuriGen Therapeutics.

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Author notes

  1. Douglas J Hilton, Warren S Alexander and Benjamin T Kile: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3050, Victoria, Australia

    Stephen J Loughran, Elizabeth A Kruse, Douglas F Hacking, Carolyn A de Graaf, Tracy A Willson, Katya J Henley, Anne K Voss, Douglas J Hilton & Benjamin T Kile

  2. Division of Cancer and Hematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3050, Victoria, Australia

    Stephen J Loughran, Craig D Hyland, Donald Metcalf & Warren S Alexander

  3. Department of Medical Biology, The University of Melbourne, Parkville, 3010, Victoria, Australia

    Stephen J Loughran, Elizabeth A Kruse, Carolyn A de Graaf, Douglas J Hilton, Warren S Alexander & Benjamin T Kile

  4. Neonatal Services, The Royal Women's Hospital, Carlton, 3053, Victoria, Australia

    Douglas F Hacking

  5. Peter MacCallum Cancer Centre, St. Andrew's Place, East Melbourne, 3002, Victoria, Australia

    Sarah Ellis

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Contributions

S.J.L., D.J.H., W.S.A. and B.T.K. designed and did research, analyzed data and wrote the paper; A.K.V. and D.M. designed and did research and analyzed data; E.A.K., D.F.H., C.A.d.G., C.D.H. and S.E. did research and analyzed data; and T.A.W. and K.J.H. did research.

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Correspondence to Benjamin T Kile.

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This work was supported by MuriGen Therapeutics, in which D.J.H., W.S.A. and B.T.K. hold equity and for which they consult.

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Loughran, S., Kruse, E., Hacking, D. et al. The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells. Nat Immunol 9, 810–819 (2008). https://doi.org/10.1038/ni.1617

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