Abstract
Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16–35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases.
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Acknowledgements
We kindly acknowledge the contributions of S. Mori in the preparation of this manuscript, M. Viltadi for technical help and C. Cecchetti, Z. Sortino and C. Rizzo for clinical sample management. We thank M. Vogel for her critical reading of the manuscript. This work was supported by AIRC 2010 (IG-10092 to C.G.-P.); PRIN program (20084XBENM_004 to R.P.); Fondazione Cariplo (2009-2667 to C.G.-P.); the Lombardy Region (ID-16871 and ID14546A to C.G.-P. and FSE Dote Ricercatori 16-AR to S.R.); Leukaemia and Lymphoma Research (UK) grants (to N.C.P.C. and J.B.); the Basic Research Program of the Korea Research Foundation (R21-2007-000-10041-0 to D.-W.K.) (2007); and Mildred Scheel Stiftung fuer Krebsforschung (Deutsche Krebshilfe, Germany, grant 109590 to N.W.).
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R.P., S.V., N.W., S.R., R.S., A.P., L.M., C.D., E.P., P.F.d.C., H.G.J., V.F., G.R.B., V.M., P.J.C. and A.J.C. performed the experiments. R.P., S.V., S.R., R.S., L.A., F.R., A.J.C., W.J.T. and N.C.P.C. performed data analysis. S.S., D.-W.K., J.B., G.G., G.P.D.M., T.H., P.J.C., E.M.P. and N.C.P.C. contributed reagents, materials and analysis tools. R.P. and C.G.-P. wrote the first draft of the manuscript. L.A. performed statistical analysis. N.C.P.C. and C.G.-P. supervised research. C.G.-P. initiated the project. All coauthors contributed to the final version of the manuscript.
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Piazza, R., Valletta, S., Winkelmann, N. et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet 45, 18–24 (2013). https://doi.org/10.1038/ng.2495
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DOI: https://doi.org/10.1038/ng.2495
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