Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes

Timothy A. Graubert; Dong Shen; Li Ding; Theresa Okeyo-Owuor; Cara L. Lunn; Jin Shao; Kilannin Krysiak; Christopher C. Harris; Daniel C. Koboldt; David E. Larson; Michael D. McLellan; David J. Dooling; Rachel M. Abbott; Robert S. Fulton; Heather Schmidt; Joelle Kalicki-Veizer; Michelle O&apos;Laughlin; Marcus Grillot; Jack Baty; Sharon Heath; John L. Frater; Talat Nasim; Daniel C. Link; Michael H. Tomasson; Peter Westervelt; John F. DiPersio; Elaine R. Mardis; Timothy J. Ley; Richard K. Wilson; Matthew J. Walter

doi:10.1038/ng.1031

Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes

Timothy A. Graubert, Dong Shen, Li Ding, Theresa Okeyo-Owuor, Cara L. Lunn, Jin Shao, Kilannin Krysiak, Christopher C. Harris, Daniel C. Koboldt, David E. Larson, Michael D. McLellan, David J. Dooling, Rachel M. Abbott, Robert S. Fulton, Heather Schmidt, Joelle Kalicki-Veizer, Michelle O'Laughlin, Marcus Grillot, Jack Baty, Sharon HeathJohn L. Frater, Talat Nasim, Daniel C. Link, Michael H. Tomasson, Peter Westervelt, John F. DiPersio, Elaine R. Mardis, Timothy J. Ley, Richard K. Wilson, Matthew J. Walter

Washington University in St Louis

Research output: Contribution to journal › Article › peer-review

495 Citations (Scopus)

Abstract

Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML associated with this mutation. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3' end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein(1,2). Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This previously unidentified, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis.

Original language	English
Pages (from-to)	53 - U77
Number of pages	5
Journal	Nature Genetics
Volume	44
Issue number	1
DOIs	https://doi.org/10.1038/ng.1031
Publication status	Published - Jan 2012

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Graubert, T. A., Shen, D., Ding, L., Okeyo-Owuor, T., Lunn, C. L., Shao, J., Krysiak, K., Harris, C. C., Koboldt, D. C., Larson, D. E., McLellan, M. D., Dooling, D. J., Abbott, R. M., Fulton, R. S., Schmidt, H., Kalicki-Veizer, J., O'Laughlin, M., Grillot, M., Baty, J., ... Walter, M. J. (2012). Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nature Genetics, 44(1), 53 - U77. https://doi.org/10.1038/ng.1031

@article{1b5ff97e71624c5bbbb55d06b072d0e2,

title = "Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes",

abstract = "Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML associated with this mutation. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3' end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein(1,2). Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This previously unidentified, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis.",

author = "Graubert, {Timothy A.} and Dong Shen and Li Ding and Theresa Okeyo-Owuor and Lunn, {Cara L.} and Jin Shao and Kilannin Krysiak and Harris, {Christopher C.} and Koboldt, {Daniel C.} and Larson, {David E.} and McLellan, {Michael D.} and Dooling, {David J.} and Abbott, {Rachel M.} and Fulton, {Robert S.} and Heather Schmidt and Joelle Kalicki-Veizer and Michelle O'Laughlin and Marcus Grillot and Jack Baty and Sharon Heath and Frater, {John L.} and Talat Nasim and Link, {Daniel C.} and Tomasson, {Michael H.} and Peter Westervelt and DiPersio, {John F.} and Mardis, {Elaine R.} and Ley, {Timothy J.} and Wilson, {Richard K.} and Walter, {Matthew J.}",

year = "2012",

month = jan,

doi = "10.1038/ng.1031",

language = "English",

volume = "44",

pages = "53 -- U77",

journal = "Nature Genetics",

issn = "1546-1718",

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Graubert, TA, Shen, D, Ding, L, Okeyo-Owuor, T, Lunn, CL, Shao, J, Krysiak, K, Harris, CC, Koboldt, DC, Larson, DE, McLellan, MD, Dooling, DJ, Abbott, RM, Fulton, RS, Schmidt, H, Kalicki-Veizer, J, O'Laughlin, M, Grillot, M, Baty, J, Heath, S, Frater, JL, Nasim, T, Link, DC, Tomasson, MH, Westervelt, P, DiPersio, JF, Mardis, ER, Ley, TJ, Wilson, RK & Walter, MJ 2012, 'Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes', Nature Genetics, vol. 44, no. 1, pp. 53 - U77. https://doi.org/10.1038/ng.1031

TY - JOUR

T1 - Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes

AU - Graubert, Timothy A.

AU - Shen, Dong

AU - Ding, Li

AU - Okeyo-Owuor, Theresa

AU - Lunn, Cara L.

AU - Shao, Jin

AU - Krysiak, Kilannin

AU - Harris, Christopher C.

AU - Koboldt, Daniel C.

AU - Larson, David E.

AU - McLellan, Michael D.

AU - Dooling, David J.

AU - Abbott, Rachel M.

AU - Fulton, Robert S.

AU - Schmidt, Heather

AU - Kalicki-Veizer, Joelle

AU - O'Laughlin, Michelle

AU - Grillot, Marcus

AU - Baty, Jack

AU - Heath, Sharon

AU - Frater, John L.

AU - Nasim, Talat

AU - Link, Daniel C.

AU - Tomasson, Michael H.

AU - Westervelt, Peter

AU - DiPersio, John F.

AU - Mardis, Elaine R.

AU - Ley, Timothy J.

AU - Wilson, Richard K.

AU - Walter, Matthew J.

PY - 2012/1

Y1 - 2012/1

N2 - Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML associated with this mutation. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3' end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein(1,2). Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This previously unidentified, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis.

AB - Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML associated with this mutation. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3' end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein(1,2). Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This previously unidentified, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis.

U2 - 10.1038/ng.1031

DO - 10.1038/ng.1031

M3 - Article

SN - 1546-1718

VL - 44

SP - 53 - U77

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes

Abstract

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