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

194 Scopus citations


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
Issue number5
StatePublished - May 11 2015
Externally publishedYes

Bibliographical note

Funding Information:
Support was provided by NIH/NHLBI (T32HL007088 to C.L.S.), Barnes-Jewish Hospital Foundation (to B.S.W., T.A.G., and M.J.W.); an NIH/NCI SPORE in Leukemia (P50CA171963 to B.S.W., T.A.G., and M.J.W.); an NIH/NCI grant (K12CA167540 to B.S.W); the Edward P. Evans Foundation (to T.A.G. and M.J.W.); a Clinical and Translational Award from the NIH National Center for Advancing Translational Sciences (UL1 TR000448 to B.S.W.); and a Howard Hughes Medical Institute Physician-Scientist Early Career Award, Leukemia and Lymphoma Society Scholar Award, Department of Defense (BM120018), and Aplastic Anemia and MDS International Foundation (to M.J.W.). Technical assistance was provided by the Alvin J. Siteman Cancer Center High Speed Cell Sorting Core and the Tissue Procurement Core supported by an NCI Cancer Center Support Grant (P30CA91842) and the Genome Institute. The authors thank Tianjiao Wang for technical assistance and Drs. Tim Ley and Dan Link for helpful scientific discussions.

Publisher Copyright:
© 2015 Elsevier Inc.


Dive into the research topics of 'Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo'. Together they form a unique fingerprint.

Cite this