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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194 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 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

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.

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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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title = "Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo",

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.}",

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: {\textcopyright} 2015 Elsevier Inc.",

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

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AU - Shirai, Cara Lunn

AU - Ley, James N.

AU - White, Brian S.

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.

N1 - 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.

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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