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.
The authors declare no competing financial interests.
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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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