Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo

Cancer Cell. 2015 May 11;27(5):631-43. doi: 10.1016/j.ccell.2015.04.008.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Hematopoiesis / genetics*
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Mice, Transgenic
  • Mutation*
  • Myelodysplastic Syndromes / genetics
  • Nuclear Proteins / genetics*
  • RNA Precursors / genetics*
  • RNA Splicing / genetics*
  • RNA, Messenger / genetics*
  • Ribonucleoproteins / genetics*
  • Splicing Factor U2AF

Substances

  • Nuclear Proteins
  • RNA Precursors
  • RNA, Messenger
  • Ribonucleoproteins
  • Splicing Factor U2AF
  • U2AF1 protein, human

Associated data

  • GEO/GSE66793