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Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms

Nature Genetics volume 45, pages 1232–1237 (2013)Cite this article

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Abstract

Cohesin is a multimeric protein complex that is involved in the cohesion of sister chromatids, post-replicative DNA repair and transcriptional regulation. Here we report recurrent mutations and deletions involving multiple components of the cohesin complex, including STAG2, RAD21, SMC1A and SMC3, in different myeloid neoplasms. These mutations and deletions were mostly mutually exclusive and occurred in 12.1% (19/157) of acute myeloid leukemia, 8.0% (18/224) of myelodysplastic syndromes, 10.2% (9/88) of chronic myelomonocytic leukemia, 6.3% (4/64) of chronic myelogenous leukemia and 1.3% (1/77) of classical myeloproliferative neoplasms. Cohesin-mutated leukemic cells showed reduced amounts of chromatin-bound cohesin components, suggesting a substantial loss of cohesin binding sites on chromatin. The growth of leukemic cell lines harboring a mutation in RAD21 (Kasumi-1 cells) or having severely reduced expression of RAD21 and STAG2 (MOLM-13 cells) was suppressed by forced expression of wild-type RAD21 and wild-type RAD21 and STAG2, respectively. These findings suggest a role for compromised cohesin functions in myeloid leukemogenesis.

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Figure 1: Genetic alterations of the cohesin complex in myeloid neoplasms.
Figure 2: Relationship between cohesin mutations and other common mutations in myeloid malignancies.
Figure 3: Abnormal cohesin expression and chromatin binding of various cohesin components in myeloid leukemic cell lines.
Figure 4: Impact of cohesin mutations on cell proliferation and karyotypes.

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References

  1. Bejar, R., Levine, R. & Ebert, B.L. Unraveling the molecular pathophysiology of myelodysplastic syndromes. J. Clin. Oncol. 29, 504–515 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Marcucci, G., Haferlach, T. & Dohner, H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J. Clin. Oncol. 29, 475–486 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Yoshida, K. et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478, 64–69 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Gruber, S., Haering, C.H. & Nasmyth, K. Chromosomal cohesin forms a ring. Cell 112, 765–777 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Nasmyth, K. & Haering, C.H. Cohesin: its roles and mechanisms. Annu. Rev. Genet. 43, 525–558 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Ström, L. et al. Postreplicative formation of cohesion is required for repair and induced by a single DNA break. Science 317, 242–245 (2007).

    Article  PubMed  Google Scholar 

  7. Watrin, E. & Peters, J.M. The cohesin complex is required for the DNA damage-induced G2/M checkpoint in mammalian cells. EMBO J. 28, 2625–2635 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dorsett, D. Cohesin, gene expression and development: lessons from Drosophila. Chromosome Res. 17, 185–200 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dorsett, D. et al. Effects of sister chromatid cohesion proteins on cut gene expression during wing development in Drosophila. Development 132, 4743–4753 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Horsfield, J.A. et al. Cohesin-dependent regulation of Runx genes. Development 134, 2639–2649 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Parelho, V. et al. Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell 132, 422–433 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Wendt, K.S. et al. Cohesin mediates transcriptional insulation by CCCTC-binding factor. Nature 451, 796–801 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Bose, T. & Gerton, J.L. Cohesinopathies, gene expression, and chromatin organization. J. Cell Biol. 189, 201–210 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Deardorff, M.A. et al. HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature 489, 313–317 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Deardorff, M.A. et al. RAD21 mutations cause a human cohesinopathy. Am. J. Hum. Genet. 90, 1014–1027 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Solomon, D.A. et al. Mutational inactivation of STAG2 causes aneuploidy in human cancer. Science 333, 1039–1043 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Beckouët, F. et al. An Smc3 acetylation cycle is essential for establishment of sister chromatid cohesion. Mol. Cell 39, 689–699 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Liu, J. et al. Transcriptional dysregulation in NIPBL and cohesin mutant human cells. PLoS Biol. 7, e1000119 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Liu, J. et al. Genome-wide DNA methylation analysis in cohesin mutant human cell lines. Nucleic Acids Res. 38, 5657–5671 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schaaf, C.A. et al. Regulation of the Drosophila enhancer of split and invected-engrailed gene complexes by sister chromatid cohesion proteins. PLoS ONE 4, e6202 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ding, L. et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481, 506–510 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Walter, M.J. et al. Clonal architecture of secondary acute myeloid leukemia. N. Engl. J. Med. 366, 1090–1098 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Welch, J.S. et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 150, 264–278 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 (2013).

  25. Walter, M.J. et al. Clonal diversity of recurrently mutated genes in myelodysplastic syndromes. Leukemia 27, 12785–1282 (2013).

    Article  Google Scholar 

  26. Barber, T.D. et al. Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers. Proc. Natl. Acad. Sci. USA 105, 3443–3448 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Heidinger-Pauli, J.M., Mert, O., Davenport, C., Guacci, V. & Koshland, D. Systematic reduction of cohesin differentially affects chromosome segregation, condensation, and DNA repair. Curr. Biol. 20, 957–963 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hadjur, S. et al. Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus. Nature 460, 410–413 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chan, D.A. & Giaccia, A.J. Harnessing synthetic lethal interactions in anticancer drug discovery. Nat. Rev. Drug Discov. 10, 351–364 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sato, Y. et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat. Genet. doi:10.1038/ng.2699 (24 June 2013).

    PubMed  PubMed Central  Google Scholar 

  31. Kent, W.J. BLAT—the BLAST-like alignment tool. Genome Res. 12, 656–664 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kumar, P., Henikoff, S. & Ng, P.C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc. 4, 1073–1081 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Adzhubei, I.A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Schwarz, J.M., Rodelsperger, C., Schuelke, M. & Seelow, D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat. Methods 7, 575–576 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Ronaghi, M. Pyrosequencing sheds light on DNA sequencing. Genome Res. 11, 3–11 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Shih, L.Y. et al. Emerging kinetics of BCR-ABL1 mutations and their effect on disease outcomes in chronic myeloid leukemia patients with imatinib failure. Leuk. Res. 37, 43–49 (2013).

    Article  CAS  PubMed  Google Scholar 

  38. Qin, J., Jones, R.C. & Ramakrishnan, R. Studying copy number variations using a nanofluidic platform. Nucleic Acids Res. 36, e116 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Dube, S., Qin, J. & Ramakrishnan, R. Mathematical analysis of copy number variation in a DNA sample using digital PCR on a nanofluidic device. PLoS ONE 3, e2876 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Totoki, Y. et al. High-resolution characterization of a hepatocellular carcinoma genome. Nat. Genet. 43, 464–469 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. 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  PubMed  Google Scholar 

  42. 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  PubMed  PubMed Central  Google Scholar 

  43. Hosoya, N. et al. Genomewide screening of DNA copy number changes in chronic myelogenous leukemia with the use of high-resolution array-based comparative genomic hybridization. Genes Chromosom. Cancer 45, 482–494 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Sanada, M. et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature 460, 904–908 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Nagae, G. et al. Tissue-specific demethylation in CpG-poor promoters during cellular differentiation. Hum. Mol. Genet. 20, 2710–2721 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Nabekura, T., Otsu, M., Nagasawa, T., Nakauchi, H. & Onodera, M. Potent vaccine therapy with dendritic cells genetically modified by the gene-silencing–resistant retroviral vector GCDNsap. Mol. Ther. 13, 301–309 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Agarwal, S. et al. Isolation, characterization, and genetic complementation of a cellular mutant resistant to retroviral infection. Proc. Natl. Acad. Sci. USA 103, 15933–15938 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Li, C. & Wong, W.H. Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc. Natl. Acad. Sci. USA 98, 31–36 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Mortazavi, A., Williams, B.A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat. Methods 5, 621–628 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Pruitt, K.D., Tatusova, T., Brown, G.R. & Maglott, D.R. NCBI Reference Sequences (RefSeq): current status, new features and genome annotation policy. Nucleic Acids Res. 40, D130–D135 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Grants-in-Aid from the Ministry of Health, Labor and Welfare of Japan and KAKENHI (23249052, 22134006 and 21790907; S.O.), the Industrial Technology Research Grant Program from the New Energy and Industrial Technology Development Organization (NEDO; S.O.) (08C46598a), NHRI-EX100-10003NI Taiwan (L.-Y.S.), the project for development of innovative research on cancer therapies (p-direct; S.O.) and the Japan Society for the Promotion of Science through the Funding Program for World-Leading Innovative R&D on Science and Technology, initiated by the Council for Science and Technology Policy (CSTP; S.O.). We thank Y. Hayashi (Gunma Children's Medical Centre), R.C. Mulligan (Harvard Medical School), S. Sugano (The University of Tokyo), M. Onodera (National Center for Child Health and Development, Japan) and L. Ström (Karolinska Institute) for providing materials. We thank Y. Yamazaki for cell sorting. We also thank Y. Mori, M. Nakamura, N. Mizota and S. Ichimura for their technical assistance and M. Ueda for encouragement.

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Authors and Affiliations

  1. Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

    Ayana Kon, Masashi Sanada, Yasunobu Nagata, Kenichi Yoshida, Yusuke Okuno, Aiko Sato-Otsubo, Yusuke Sato & Seishi Ogawa

  2. Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan

    Lee-Yung Shih

  3. Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

    Masashi Minamino, Masashige Bando, Ryuichiro Nakato & Katsuhiko Shirahige

  4. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Kyoto-shi Sakyo-ku, Kyoto, Japan

    Masashi Sanada & Seishi Ogawa

  5. Laboratory of DNA Information Analysis, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan

    Yuichi Shiraishi, Teppei Shimamura, Kenichi Chiba & Satoru Miyano

  6. Department of Pathology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

    Shumpei Ishikawa & Aiko Nishimoto

  7. Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

    Shumpei Ishikawa

  8. Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan

    Genta Nagae & Hiroyuki Aburatani

  9. Munich Leukemia Laboratory, Munich, Germany

    Claudia Haferlach, Tamara Alpermann & Torsten Haferlach

  10. Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany

    Daniel Nowak, Florian Nolte & Wolf-Karsten Hofmann

  11. Division of Biomedical Information Analysis, Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Aoba-ku, Sendai, Japan

    Masao Nagasaki

  12. Laboratory of Sequence Data Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan

    Hiroko Tanaka & Satoru Miyano

  13. Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan

    Ryo Yamamoto, Tomoyuki Yamaguchi & Hiromitsu Nakauchi

  14. Stem Cell and Organ Regeneration Project, Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Agency (JST), Chiyoda-ku, Tokyo, Japan

    Tomoyuki Yamaguchi & Hiromitsu Nakauchi

  15. Stem Cell Bank, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan

    Makoto Otsu

  16. Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

    Naoshi Obara, Mamiko Sakata-Yanagimoto & Shigeru Chiba

  17. Division of Hematology, Department of Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan

    Tsuyoshi Nakamaki & Hiraku Mori

  18. Division of Hematology, Tokyo Metropolitan Ohtsuka Hospital, Toshima-ku, Tokyo, Japan

    Ken Ishiyama & Shuichi Miyawaki

  19. Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, California, USA

    H Phillip Koeffler

  20. National University of Singapore, Cancer Science Institute of Singapore, Singapore

    H Phillip Koeffler

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  1. Ayana Kon
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Contributions

A.K., Y.N., K.Y., A.S.-O., Y. Sato and M.S. processed and analyzed genetic materials and performed sequencing and SNP array analysis. Y. Shiraishi, Y.O., R.N., A.S.-O., H.T., T.S., K.C., M.N. and S. Miyano performed bioinformatics analyses of the sequencing data. L.-Y.S. performed pyrosequencing analysis, and A.N. and S.I. performed digital PCR. G.N. and H.A. performed methylation analysis. M.M., M.B. and K.S. performed studies on protein expression of cohesin components. A.K., M.S., T.Y., R.Y., M.O. and H.N. were involved in the functional studies. A.K. and A.S.-O. performed expression microarray experiments and their analyses. L.-Y.S., D.N., T.A., C.H., F.N., W.-K.H., T.H., H.P.K., T.N., H.M., S. Miyawaki, M.S.-Y., K.I., N.O. and S.C. collected specimens and were involved in project planning. A.K., L.-Y.S., M.M., A.S.-O. and S.O. generated figures and tables. S.O. led the entire project, and A.K. and S.O. wrote the manuscript. All authors participated in the discussion and interpretation of the data.

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Correspondence to Seishi Ogawa.

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Kon, A., Shih, LY., Minamino, M. et al. Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. Nat Genet 45, 1232–1237 (2013). https://doi.org/10.1038/ng.2731

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