Abstract
Juvenile myelomonocytic leukemia (JMML) is an intractable pediatric leukemia with poor prognosis1 whose molecular pathogenesis is poorly understood, except for somatic or germline mutations of RAS pathway genes, including PTPN11, NF1, NRAS, KRAS and CBL, in the majority of cases2,3,4. To obtain a complete registry of gene mutations in JMML, whole-exome sequencing was performed for paired tumor-normal DNA from 13 individuals with JMML (cases), which was followed by deep sequencing of 8 target genes in 92 tumor samples. JMML was characterized by a paucity of gene mutations (0.85 non-silent mutations per sample) with somatic or germline RAS pathway involvement in 82 cases (89%). The SETBP1 and JAK3 genes were among common targets for secondary mutations. Mutations in the latter were often subclonal and may be involved in the progression rather than the initiation of leukemia, and these mutations associated with poor clinical outcome. Our findings provide new insights into the pathogenesis and progression of JMML.
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Acknowledgements
We thank the subjects and their parents for participating in this study. This work was supported by the Research on Measures for Intractable Diseases Project from the Ministry of Health, Labor and Welfare, by Grants-in-Aid from the Ministry of Health, Labor and Welfare of Japan and KAKENHI (23249052, 22134006 and 21790907), by the Project for the Development of Innovative Research on Cancer Therapeutics (P-DIRECT) and by the Japan Society for the Promotion of Science through the Funding Program for World-Leading Innovative R&D on Science and Technology.
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H.S., Y.O., H. Muramatsu, K.Y., M.T., A.K. and M.S. designed and performed the research, analyzed the data and wrote the manuscript. Y.S., K.C., H.T. and S.M. performed bioinformatics analyses of the resequencing data. X.W. and Y.X. performed Sanger sequencing. S.D., A.H., K.N., Y.T. and N.Y. collected specimens and performed the research. H. Makishima and J.P.M. designed the research and analyzed the data. S.O. and S.K. led the entire project and wrote the manuscript.
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Sakaguchi, H., Okuno, Y., Muramatsu, H. et al. Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet 45, 937–941 (2013). https://doi.org/10.1038/ng.2698
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DOI: https://doi.org/10.1038/ng.2698
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