title: Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo.
abstract: Heterozygous somatic mutations in the spliceosome gene U2AF1 occur in ∼ 11% of patients with myelodysplastic syndromes (MDS), the most common adult myeloid malignancy. It is unclear how these mutations contribute to disease. We examined in vivo hematopoietic consequences of the most common U2AF1 mutation using a doxycycline-inducible transgenic mouse model. Mice expressing mutant U2AF1(S34F) display altered hematopoiesis and changes in pre-mRNA splicing in hematopoietic progenitor cells by whole transcriptome analysis (RNA-seq). Integration with human RNA-seq datasets determined that common mutant U2AF1-induced splicing alterations are enriched in RNA processing genes, ribosomal genes, and recurrently mutated MDS and acute myeloid leukemia-associated genes. These findings support the hypothesis that mutant U2AF1 alters downstream gene isoform expression, thereby contributing to abnormal hematopoiesis in patients with MDS.
authors.affiliation: Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: Cara Lunn
authors.initials: CL
authors.lastname: Shirai
authors.affiliation: Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: James N
authors.initials: JN
authors.lastname: Ley
authors.affiliation: Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA; The Genome Institute, Washington University, St. Louis, MO 63110, USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: White
authors.affiliation: Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: Sanghyun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Tibbitts
authors.affiliation: Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Shao
authors.affiliation: Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ndonwi
authors.affiliation: Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Wadugu
authors.affiliation: Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Duncavage
authors.affiliation: Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Okeyo-Owuor
authors.affiliation: Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: Tuoen
authors.initials: T
authors.lastname: Liu
authors.affiliation: The Genome Institute, Washington University, St. Louis, MO 63110, USA.
authors.forename: Malachi
authors.initials: M
authors.lastname: Griffith
authors.affiliation: The Genome Institute, Washington University, St. Louis, MO 63110, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: McGrath
authors.affiliation: The Genome Institute, Washington University, St. Louis, MO 63110, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Magrini
authors.affiliation: The Genome Institute, Washington University, St. Louis, MO 63110, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.affiliation: The Genome Institute, Washington University, St. Louis, MO 63110, USA.
authors.forename: Catrina
authors.initials: C
authors.lastname: Fronick
authors.affiliation: The Genome Institute, Washington University, St. Louis, MO 63110, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: O'Laughlin
authors.affiliation: Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
authors.affiliation: Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA. Electronic address: mjwalter@dom.wustl.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walter
mesh_terms: D000818:Animals; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D008822:Mice, Transgenic; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D012322:RNA Precursors / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D012261:Ribonucleoproteins / Q000235:genetics*; D000072668:Splicing Factor U2AF
chemical_list: D009687:Nuclear Proteins; D012322:RNA Precursors; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human