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

doi:10.1016/j.ccell.2015.04.008

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

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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 language	English (US)
Pages (from-to)	631-643
Number of pages	13
Journal	Cancer Cell
Volume	27
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2015.04.008
State	Published - May 11 2015
Externally published	Yes

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Publisher Copyright:
© 2015 Elsevier Inc.

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Shirai, C. L., Ley, J. N., White, B. S., Kim, S., Tibbitts, J., Shao, J., Ndonwi, M., Wadugu, B., Duncavage, E. J., Okeyo-Owuor, T., Liu, T., Griffith, M., McGrath, S., Magrini, V., Fulton, R. S., Fronick, C., O'Laughlin, M., Graubert, T. A., & Walter, M. J. (2015). Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo. Cancer Cell, 27(5), 631-643. https://doi.org/10.1016/j.ccell.2015.04.008

Shirai, CL, Ley, JN, White, BS, Kim, S, Tibbitts, J, Shao, J, Ndonwi, M, Wadugu, B, Duncavage, EJ, Okeyo-Owuor, T, Liu, T, Griffith, M, McGrath, S, Magrini, V, Fulton, RS, Fronick, C, O'Laughlin, M, Graubert, TA & Walter, MJ 2015, 'Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo', Cancer Cell, vol. 27, no. 5, pp. 631-643. https://doi.org/10.1016/j.ccell.2015.04.008

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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.",

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

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doi = "10.1016/j.ccell.2015.04.008",

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AU - Shirai, Cara Lunn

AU - Ley, James N.

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AU - Kim, Sanghyun

AU - Tibbitts, Justin

AU - Shao, Jin

AU - Ndonwi, Matthew

AU - Wadugu, Brian

AU - Duncavage, Eric J.

AU - Okeyo-Owuor, Theresa

AU - Liu, Tuoen

AU - Griffith, Malachi

AU - McGrath, Sean

AU - Magrini, Vincent

AU - Fulton, Robert S.

AU - Fronick, Catrina

AU - O'Laughlin, Michelle

AU - Graubert, Timothy A.

AU - Walter, Matthew J.

PY - 2015/5/11

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N2 - 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.

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

Abstract

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