title: WT1 regulates murine hematopoiesis via maintenance of VEGF isoform ratio.
abstract: Mutations in the Wilms tumor suppressor 1 (WT1) gene are as frequent in acute myeloid leukemia (AML) as in nephroblastma and predict poor prognosis. However, the role of WT1 in hematopoiesis remains unclear. We show that Wt1-deficient mouse embryonic stem cells exhibit reduced hematopoietic potential caused by vascular endothelial growth factor A (Vegf-a)-dependent apoptosis of hematopoietic progenitor cells associated with overproduction of the Vegf-a120 isoform. We demonstrate that Wt1 promotes exon inclusion using a Vegf-a minigene-based splicing assay. These data identify a critical role for Wt1 in hematopoiesis and Vegf-a as a cellular RNA whose splicing is potentially regulated by Wt1. The correction of Wt1 deficiency by treatment with exogenous Vegf-a protein indicates that the Wt1/Vegf-a axis is a molecular pathway that could be exploited for the management/treatment of poor prognosis AMLs.
authors.affiliation: Newcastle University Institute of Genetic Medicine, International Centre for Life, Newcastle, United Kingdom.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Cunningham
authors.forename: Ilaria
authors.initials: I
authors.lastname: Palumbo
authors.forename: Michela
authors.initials: M
authors.lastname: Grosso
authors.forename: Nicholas
authors.initials: N
authors.lastname: Slater
authors.forename: Colin G
authors.initials: CG
authors.lastname: Miles
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D053595:Embryonic Stem Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006410:Hematopoiesis / Q000502:physiology*; D051379:Mice; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D025721:WT1 Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D025721:WT1 Proteins