Frequent pathway mutations of splicing machinery in myelodysplasia (original) (raw)

Accession codes

Primary accessions

DDBJ/GenBank/EMBL

Gene Expression Omnibus

Data deposits

Sequence data have been deposited in the DDBJ repository under accession number DRA000433. Microarray data have been deposited in the GEO database under accession numbers GSE31174 (for SNP arrays), GSE31171 (for exon arrays) and GSE31172 (for expression arrays).

References

1. Corey, S. J. et al. Myelodysplastic syndromes: the complexity of stem-cell diseases. Nature Rev. Cancer 7, 118–129 (2007)
   Article CAS Google Scholar
2. Ma, X., Does, M., Raza, A. & Mayne, S. T. Myelodysplastic syndromes: incidence and survival in the United States. Cancer 109, 1536–1542 (2007)
   Article Google Scholar
3. Bejar, R., Levine, R. & Ebert, B. L. Unraveling the molecular pathophysiology of myelodysplastic syndromes. J. Clin. Oncol. 29, 504–515 (2011)
   Article CAS Google Scholar
4. Sanada, M. et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature 460, 904–908 (2009)
   Article CAS ADS Google Scholar
5. Campbell, P. J. et al. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nature Genet. 40, 722–729 (2008)
   Article CAS Google Scholar
6. Chapman, M. A. et al. Initial genome sequencing and analysis of multiple myeloma. Nature 471, 467–472 (2011)
   Article CAS ADS Google Scholar
7. Lee, W. et al. The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature 465, 473–477 (2010)
   Article CAS ADS Google Scholar
8. Ley, T. J. et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 456, 66–72 (2008)
   Article CAS ADS Google Scholar
9. Metzker, M. L. Sequencing technologies — the next generation. Nature Rev. Genet. 11, 31–46 (2010)
   Article CAS Google Scholar
10. Shendure, J. & Ji, H. Next-generation DNA sequencing. Nature Biotechnol. 26, 1135–1145 (2008)
    Article CAS Google Scholar
11. Shah, S. P. et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461, 809–813 (2009)
    Article CAS ADS Google Scholar
12. Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011)
    Article CAS ADS Google Scholar
13. Ley, T. J. et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433 (2010)
    Article CAS Google Scholar
14. Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009)
    Article CAS Google Scholar
15. Yan, X. J. et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nature Genet. 43, 309–315 (2011)
    Article CAS Google Scholar
16. Puente, X. S. et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475, 101–105 (2011)
    Article CAS Google Scholar
17. Nannya, Y. et al. A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays. Cancer Res. 65, 6071–6079 (2005)
    Article CAS Google Scholar
18. Yamamoto, G. et al. Highly sensitive method for genomewide detection of allelic composition in nonpaired, primary tumor specimens by use of Affymetrix single-nucleotide-polymorphism genotyping microarrays. Am. J. Hum. Genet. 81, 114–126 (2007)
    Article CAS Google Scholar
19. Wahl, M. C., Will, C. L. & Luhrmann, R. The spliceosome: design principles of a dynamic RNP machine. Cell 136, 701–718 (2009)
    Article CAS Google Scholar
20. Tronchère, H., Wang, J. & Fu, X. D. A protein related to splicing factor U2AF35 that interacts with U2AF65 and SR proteins in splicing of pre-mRNA. Nature 388, 397–400 (1997)
    Article ADS Google Scholar
21. Bevilacqua, L. et al. A population-specific HTR2B stop codon predisposes to severe impulsivity. Nature 468, 1061–1066 (2010)
    Article CAS ADS Google Scholar
22. Calvo, S. E. et al. High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nature Genet. 42, 851–858 (2010)
    Article CAS Google Scholar
23. Haase, D. et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 110, 4385–4395 (2007)
    Article CAS Google Scholar
24. Xiao, R. et al. Splicing regulator SC35 is essential for genomic stability and cell proliferation during mammalian organogenesis. Mol. Cell. Biol. 27, 5393–5402 (2007)
    Article CAS Google Scholar
25. Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nature Genet. 42, 181–185 (2010)
    Article CAS Google Scholar
26. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005)
    Article CAS ADS Google Scholar
27. Maquat, L. E. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nature Rev. Mol. Cell Biol. 5, 89–99 (2004)
    Article CAS Google Scholar
28. Ema, H. et al. Adult mouse hematopoietic stem cells: purification and single-cell assays. Nature Protocols 1, 2979–2987 (2007)
    Article Google Scholar
29. Chen, M. & Manley, J. L. Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nature Rev. Mol. Cell Biol. 10, 741–754 (2009)
    Article CAS Google Scholar
30. Ni, J. Z. et al. Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay. Genes Dev. 21, 708–718 (2007)
    Article CAS Google Scholar
31. He, H. et al. Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I. Science 332, 238–240 (2011)
    Article CAS ADS Google Scholar
32. Edery, P. et al. Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA. Science 332, 240–243 (2011)
    Article CAS ADS Google Scholar
33. David, C. J. & Manley, J. L. Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev. 24, 2343–2364 (2010)
    Article CAS Google Scholar
34. Pajares, M. J. et al. Alternative splicing: an emerging topic in molecular and clinical oncology. Lancet Oncol. 8, 349–357 (2007)
    Article CAS Google Scholar
35. Shen, H., Zheng, X., Luecke, S. & Green, M. R. The U2AF35-related protein Urp contacts the 3′ splice site to promote U12-type intron splicing and the second step of U2-type intron splicing. Genes Dev. 24, 2389–2394 (2010)
    Article CAS Google Scholar
36. Barlow, J. L. et al. A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q− syndrome. Nature Med. 16, 59–66 (2010)
    Article CAS Google Scholar
37. Ebert, B. L. et al. Identification of RPS14 as a 5q− syndrome gene by RNA interference screen. Nature 451, 335–339 (2008)
    Article CAS ADS Google Scholar

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Acknowledgements

This work was supported by Grant-in-Aids from the Ministry of Health, Labor and Welfare of Japan and from the Ministry of Education, Culture, Sports, Science and Technology, and also by the Japan Society for the Promotion of Science (JSPS) through the ‘Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program)’, initiated by the Council for Science and Technology Policy (CSTP). pGCDNsamIRESEGFP vector was a gift from M. Onodera. We thank Y. Mori, O. Hagiwara, M. Nakamura and N. Mizota for their technical assistance. We are also grateful to K. Ikeuchi and M. Ueda for their continuous encouragement throughout the study.

Author information

Author notes

1. Kenichi Yoshida, Masashi Sanada, Yuichi Shiraishi, Daniel Nowak and Yasunobu Nagata: These authors contributed equally to this work.

Authors and Affiliations

1. Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan ,
   Kenichi Yoshida, Masashi Sanada, Yasunobu Nagata, Yusuke Sato, Aiko Sato-Otsubo, Ayana Kon, Masashi Shiosaka, Ryoichiro Kawahata & Seishi Ogawa
2. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan ,
   Yuichi Shiraishi & Satoru Miyano
3. Department of Hematology and Oncology, Medical Faculty Manheim of the University of Heidelberg, 1–3 Theodor-Kutzer-Ufer, Mannheim 68167, Germany,
   Daniel Nowak, Florian Nolte & Wolf-Karsten Hofmann
4. Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan,
   Ryo Yamamoto, Makoto Otsu & Hiromitsu Nakauchi
5. Laboratory of Functional Genomics, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan ,
   Masao Nagasaki
6. Laboratory of Sequence Data Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan ,
   George Chalkidis & Satoru Miyano
7. Division of Systems Biomedical Technology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan,
   Yutaka Suzuki & Sumio Sugano
8. Nakauchi Stem Cell and Organ Regeneration Project, Exploratory Research for Advanced Technology, Japan Science and Technology Agency, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan ,
   Tomoyuki Yamaguchi & Hiromitsu Nakauchi
9. Department of Hematology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki, 305-8571, Japan,
   Naoshi Obara, Mamiko Sakata-Yanagimoto & Shigeru Chiba
10. Division of Hematology, Tokyo Metropolitan Ohtsuka Hospital, 2-8-1 Minami-Ohtsuka, Toshima-ku, Tokyo 170-0005, Japan,
    Ken Ishiyama & Shuichi Miyawaki
11. Division of Hematology, Internal Medicine, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa 227-8501, Japan,
    Hiraku Mori
12. Munich Leukemia Laboratory, Max-Lebsche-Platz 31, Munich 81377, Germany ,
    Claudia Haferlach & Torsten Haferlach
13. Hematology/Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, California 90048, USA ,
    H. Phillip Koeffler
14. National University of Singapore, Cancer Science Institute of Singapore, 28 Medical Drive, Singapore 117456, Singapore ,
    H. Phillip Koeffler
15. Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, 199 Tung Hwa North Rd, Taipei 105, Taiwan,
    Lee-Yung Shih

Authors

1. Kenichi Yoshida
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2. Masashi Sanada
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3. Yuichi Shiraishi
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4. Daniel Nowak
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5. Yasunobu Nagata
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6. Ryo Yamamoto
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7. Yusuke Sato
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8. Aiko Sato-Otsubo
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9. Ayana Kon
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10. Masao Nagasaki
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11. George Chalkidis
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12. Yutaka Suzuki
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13. Masashi Shiosaka
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14. Ryoichiro Kawahata
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15. Tomoyuki Yamaguchi
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16. Makoto Otsu
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17. Naoshi Obara
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18. Mamiko Sakata-Yanagimoto
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19. Ken Ishiyama
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20. Hiraku Mori
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21. Florian Nolte
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22. Wolf-Karsten Hofmann
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23. Shuichi Miyawaki
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24. Sumio Sugano
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25. Claudia Haferlach
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26. H. Phillip Koeffler
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27. Lee-Yung Shih
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28. Torsten Haferlach
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29. Shigeru Chiba
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30. Hiromitsu Nakauchi
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31. Satoru Miyano
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32. Seishi Ogawa
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Contributions

Y.Sh., Y.Sa., A.S.-O., Y.N., M.N., G.C., R.K. and S.Miyano were committed to bioinformatics analyses of resequencing data. M.Sa., A.S.-O. and Y.Sa. performed microarray experiments and their analyses. R.Y., T.Y., M.O., M.Sa., A.K., M.Sh. and H.N. were involved in the functional analyses of U2AF35 mutants. N.O., M.S.-Y., K.I., H.M., W.-K.H., F.N., D.N., T.H., C.H., S.Miyawaki, S.C., H.P.K. and L.-Y.S. collected specimens and were also involved in planning the project. K.Y., Y.N., Y.Su., A.S.-O. and S.S. processed and analysed genetic materials, library preparation and sequencing. K.Y., M.Sa., Y.Sh., A.S.-O., Y. Sa. and S.O. generated figures and tables. S.O. led the entire project and wrote the manuscript. All authors participated in the discussion and interpretation of the data and the results.

Corresponding author

Correspondence toSeishi Ogawa.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Methods 1-8 (see Contents for more details), additional references, Supplementary Figures 1-18 with legends and Supplementary Tables 1-11. (PDF 7293 kb)

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Yoshida, K., Sanada, M., Shiraishi, Y. et al. Frequent pathway mutations of splicing machinery in myelodysplasia.Nature 478, 64–69 (2011). https://doi.org/10.1038/nature10496

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• Received: 07 June 2011
• Accepted: 24 August 2011
• Published: 11 September 2011
• Issue Date: 06 October 2011
• DOI: https://doi.org/10.1038/nature10496