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

Cara Lunn Shirai, James N. Ley, Brian S. White, Sanghyun Kim, Justin Tibbitts, Jin Shao, Matthew Ndonwi, Brian Wadugu, Eric J. Duncavage, Theresa Okeyo-Owuor, Tuoen Liu, Malachi Griffith, Sean McGrath, Vincent Magrini, Robert S. Fulton, Catrina Fronick, Michelle O'Laughlin, Timothy A. Graubert, Matthew J. Walter

Research output: Contribution to journalArticlepeer-review

140 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)631-643
Number of pages13
JournalCancer Cell
Volume27
Issue number5
DOIs
StatePublished - May 11 2015
Externally publishedYes

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