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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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.

Author information


  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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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Seishi Ogawa.

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