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

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

Author information

1
Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
2
Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA; The Genome Institute, Washington University, St. Louis, MO 63110, USA.
3
Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, USA.
4
The Genome Institute, Washington University, St. Louis, MO 63110, USA.
5
Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, USA.
6
Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA. Electronic address: mjwalter@dom.wustl.edu.

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.

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PMID:
25965570
PMCID:
PMC4430854
DOI:
10.1016/j.ccell.2015.04.008
[Indexed for MEDLINE]
Free PMC Article

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