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ERG Is a Megakaryocytic Oncogene

¹ Molecular Haematology and Cancer Biology Unit, University College London Institute of Child Health and Great Ormond Street Hospital for Children; ² Immunology and Infection Section, Division of Cell and Molecular Biology, Imperial College, London, United Kingdom; and ³ Department of Pediatric Hemato-Oncology and the Cancer Research Center, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Requests for reprints: Hugh J.M. Brady, Immunology and Infection Section, Division of Cell and Molecular Biology, Sir Alexander Fleming Building, Imperial College, London SW7 2AZ, United Kingdom. Phone: 44-20-75943777; Fax: 44-20-75842056; E-mail: h.brady{at}imperial.ac.uk.

Key Words: megakaryocytes • GATA-1 • ERG • leukemia • AMKL

Ets-related gene (ERG) is a member of the ETS transcription factor gene family located on Hsa21. ERG is known to have a crucial role in establishing definitive hematopoiesis and is required for normal megakaryopoiesis. Truncated forms of ERG are associated with multiple cancers such as Ewing's sarcoma, prostate cancer, and leukemia as part of oncogenic fusion translocations. Increased expression of ERG is highly indicative of poor prognosis in acute myeloid leukemia and ERG is expressed in acute megakaryoblastic leukemia (AMKL); however, it is unclear if expression of ERG per se has a leukemogenic activity. We show that ectopic expression of ERG in fetal hematopoietic progenitors promotes megakaryopoiesis and that ERG alone acts as a potent oncogene in vivo leading to rapid onset of leukemia in mice. We observe that the endogenous ERG is required for the proliferation and maintenance of AMKL cell lines. ERG also strongly cooperates with the GATA1s mutated protein, found in Down syndrome AMKL, to immortalize megakaryocyte progenitors, suggesting that the additional copy of ERG in trisomy 21 may have a role in Down syndrome AMKL. These data suggest that ERG is a hematopoietic oncogene that may play a direct role in myeloid leukemia pathogenesis. [Cancer Res 2009;69(11):4665–73]