Abstract
Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a majority of cases, TAM may evolve as non-self-limiting AMKL after spontaneous remission (DS-AMKL). Pathogenesis of these Down syndrome–related myeloid disorders is poorly understood, except for GATA1 mutations found in most cases. Here we report genomic profiling of 41 TAM, 49 DS-AMKL and 19 non-DS-AMKL samples, including whole-genome and/or whole-exome sequencing of 15 TAM and 14 DS-AMKL samples. TAM appears to be caused by a single GATA1 mutation and constitutive trisomy 21. Subsequent AMKL evolves from a pre-existing TAM clone through the acquisition of additional mutations, with major mutational targets including multiple cohesin components (53%), CTCF (20%), and EZH2, KANSL1 and other epigenetic regulators (45%), as well as common signaling pathways, such as the JAK family kinases, MPL, SH2B3 (LNK) and multiple RAS pathway genes (47%).
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NCBI Reference Sequence
Change history
30 October 2013
In the version of this article initially published, the discussion of cited reference 52 should also have noted that the work "reported accumulation of additional somatic mutations (including single cases of SMC3 and EZH2 mutation) during progression from TAM to DS-AMKL." The error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank Y. Mori, M. Nakamura, O. Hagiwara and N. Mizota for their technical assistance. This work was supported by the Research on Measures for Intractable Diseases Project and Health and Labor Sciences Research grants (Research on Intractable Diseases) from the Ministry of Health, Labour and Welfare, by Grants-in-Aid from the Ministry of Health, Labor and Welfare of Japan and KAKENHI (22134006, 23249052, 23118501, 23390266 and 25461579) and by the Japan Society for the Promotion of Science (JSPS) through the Funding Program for World-Leading Innovative Research and Development on Science and Technology (FIRST Program), initiated by the Council for Science and Technology Policy (CSTP) and research grants from the Japan Science and Technology Agency CREST.
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Y.O., Y. Shiraishi, A.S.-O., K.C., H.T. and S.M. performed bioinformatics analyses of the resequencing data. M.S., A.S.-O., Y. Sato, A.H. and H.M. performed microarray experiments and analyses. R.K. and A.H. performed RT-PCR analyses. M.P., K. Terui, R.W., D.H., K.N., H.K., K. Tsukamoto, S.A., K. Kawakami, K. Kato, R.N., S.I., Y.H., S.K. and E.I. collected specimens and were involved in planning the project. K.Y., T.T., H.S., Y.N. and N.S. processed and analyzed genetic materials, prepared the library and performed sequencing. K.Y., T.T., Y.O., A.K. and S.O. generated figures and tables. E.I. and S.O. led the entire project. K.Y. and S.O. wrote the manuscript. All authors participated in discussions and interpretation of the data and results.
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Yoshida, K., Toki, T., Okuno, Y. et al. The landscape of somatic mutations in Down syndrome–related myeloid disorders. Nat Genet 45, 1293–1299 (2013). https://doi.org/10.1038/ng.2759
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DOI: https://doi.org/10.1038/ng.2759
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