Fli-1 is required for murine vascular and megakaryocytic development and is hemizygously deleted in patients with thrombocytopenia

The ETS gene Fli-1 is involved in the induction of erythroleukemia in mice by Friend murine leukemia virus and Ewings sarcoma in children. Mice with a targeted null mutation in the Fli-1 locus die at day 11.5 of embryogenesis with loss of vascular integrity leading to bleeding within the vascular pl exus of the cerebral meninges and specific downregulation of Tek/Tie-2, the receptor for angiopoietin-1. We also show that dysmegakaryopoiesis in Fli- 1 null embryos resembles that frequently seen in patients with terminal del etions of 11q (Jacobsen or Paris-Trousseau Syndrome). We map the megakaryoc ytic defects in 14 Jacobsen patients to a minimal region on 11q that includ es the Fli-1 gene and suggest that dysmegakaryopoiesis in these patients ma y be caused by hemizygous loss of Fli-1.