Abstract
Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and could therefore be candidates for experimental therapies. In addition, few molecular pathways aside from the RAS-MAPK pathway have been identified that could serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia to expand knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, splicing, Polycomb repressive complex 2 (PRC2) and transcription. Notably, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.
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Change history
07 December 2015
In the version of this article initially published, two patients were stated on page 5 to have been excluded owing to insufficient follow-up data. These patients were included in the final analysis, but two additional patients were excluded owing to the presence of Noonan syndrome. On page 6, monosomy 7 was incorrectly listed as a significant factor in event-free and overall survival, but this factor was no longer significant after removing the patients with Noonan syndrome. The Online Methods incorrectly referred to "Data from patient AAML0122" instead of data from patients enrolled on AAML0122. The errors have been corrected in the HTML and PDF versions of the rticle.
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Acknowledgements
The authors thank the patients and their families for participating in this research, without whom this work would not have been possible. In addition, A. Ikeda, E. Raetz, N. Bunin and J. Finkelstein all assisted in this research by providing invaluable patient samples.
This work was supported by the Carlos Slim Foundation in Mexico as part of the Slim Initiative for Genomic Medicine; the St. Baldrick's Foundation (E.S.); Alex's Lemonade Stand Foundation (E.S.); the Leukemia and Lymphoma Society (grants 6059-09 and 6466-15) (M.L.L.) and a Leukemia and Lymphoma Society Scholar award (K.S.)); US National Institutes of Health, National Cancer Institute grants T32CA128583 (E.S.) and R01CA173085 (M.L.L.), National Cancer Institute Cancer Center Support grant 5P30CA082103, Children's Oncology Group (COG) Statistics and Data Center grant 1U10CA180899 (T.A.A.), COG Chair's Grant 5U10CA098543 (T.A.A.) and US National Institutes of Health grant P30CA82103 (A.B.O.); the Frank A. Campini Foundation (E.S. and M.L.L.); Hyundai Hope on Wheels (M.L.L.); and a University of California San Francisco Dean's Commitment to the Center for Advanced Technologies facility.
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E.S., L.C.G., T.M., E.E., A.Y., K.B. and S.L.A. performed the experiments. E.S., A.N.T.-W., Y.-D.W., T.M., M.R., A.B.O., Y.L., J.M., R.B.G. and T.A.A. performed data analysis. G.A., M.B., P.A.B., B.C., T.C., G.V.D., P.D.E., M.N.F., R.K.G., R.J.H., J.H., C.H., Y.L.L., Y.H.M., D.H.M., P.M., E.R.N., P.A.R., R.J.S., K.C.S., C.M.T. and J.A.T. contributed reagents, materials and analysis tools. E.S., A.N.T.-W. and M.L.L. wrote the first draft of the manuscript. T.Y.C. performed statistical analysis. J.F.C., C.S., G.G., T.A.G., T.R.G., K.S. and M.L.L. supervised research. S.S. and S.R.O. managed the project. All coauthors contributed to the final version of the manuscript.
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Stieglitz, E., Taylor-Weiner, A., Chang, T. et al. The genomic landscape of juvenile myelomonocytic leukemia. Nat Genet 47, 1326–1333 (2015). https://doi.org/10.1038/ng.3400
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DOI: https://doi.org/10.1038/ng.3400
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