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Somatic SETBP1 mutations in myeloid malignancies

Abstract

Here we report whole-exome sequencing of individuals with various myeloid malignancies and identify recurrent somatic mutations in SETBP1, consistent with a recent report on atypical chronic myeloid leukemia (aCML)1. Closely positioned somatic SETBP1 mutations encoding changes in Asp868, Ser869, Gly870, Ile871 and Asp880, which match germline mutations in Schinzel-Giedion syndrome (SGS)2, were detected in 17% of secondary acute myeloid leukemias (sAML) and 15% of chronic myelomonocytic leukemia (CMML) cases. These results from deep sequencing demonstrate a higher mutational detection rate than reported with conventional sequencing methodology3,4,5. Mutant cases were associated with advanced age and monosomy 7/deletion 7q (–7/del(7q)) constituting poor prognostic factors. Analysis of serially collected samples indicated that SETBP1 mutations were acquired during leukemic evolution. Transduction with mutant Setbp1 led to the immortalization of mouse myeloid progenitors that showed enhanced proliferative capacity compared to cells transduced with wild-type Setbp1. Somatic mutations of SETBP1 seem to cause gain of function, are associated with myeloid leukemic transformation and convey poor prognosis in myelodysplastic syndromes (MDS) and CMML.

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Figure 1: Somatic SETBP1 mutations as detected by next-generation whole-exome sequencing and Sanger sequencing.
Figure 2: The relationship of SETBP1 mutations with other common mutations.
Figure 3: Impact of SETBP1 mutations on clinical outcome.
Figure 4: Immortalization of mouse myeloid progenitors by SETBP1 mutations.

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Acknowledgements

We thank T. Yamaguchi (The University of Tokyo) for providing CS-Ubc lentivirus vector. This work was supported by US National Institutes of Health (NIH) grants RO1 HL-082983 (J.P.M.), U54 RR019391 (J.P.M.), K24 HL-077522 (J.P.M.) and RO1 CA-143193 (Y.D.), by a grant from the AA & MDS International Foundation, by the Robert Duggan Charitable Fund (J.P.M.), by a Scott Hamilton CARES grant (H. Makishima) and by Grants-in-Aid from the Ministry of Health, Labor and Welfare of Japan and KAKENHI (23249052, 22134006 and 21790907; S.O.), the project for the development of innovative research on cancer therapies (p-direct; S.O.), the Japan Society for the Promotion of Science (JSPS) 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.), NHRI-EX100-10003NI Taiwan (L.-Y.S.) and Uniformed Services University of the Health Sciences Pediatrics grant KM86GI (Y.D.). The results presented here are partly based on data generated by The Cancer Genome Atlas (TCGA) pilot project established by the National Cancer Institute and the National Human Genome Research Institute. Information about TCGA and the investigators and institutions that constitute the TCGA research network can be found at http://cancergenome.nih.gov/.

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H. Makishima and K.Y. designed research, performed research, collected data, performed statistical analysis and wrote the manuscript. Y.O., N.N., K.P.N., B.P., K.O.G., B.A.V., A.J., I.G.-S., Y. Shiraishi, Y.N., M.S., M.T., K.C., H.T., H. Muramatsu, H.S., S.M. and L.-Y.S. performed research and analyzed data. K.G. and H. Mori collected data. M.A.S., R.L.P., M.A.M., S.K. and Y. Saunthararajah designed research, analyzed and interpreted data, and wrote the manuscript. Y.D., S.O. and J.P.M. designed research, contributed analytical tools, collected data, analyzed and interpreted data, and wrote the manuscript.

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Correspondence to Yang Du, Seishi Ogawa or Jaroslaw P Maciejewski.

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Makishima, H., Yoshida, K., Nguyen, N. et al. Somatic SETBP1 mutations in myeloid malignancies. Nat Genet 45, 942–946 (2013). https://doi.org/10.1038/ng.2696

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