The genetics behind the progression of myelodysplasia to secondary acute myeloid leukemia (sAML) is poorly understood. In this study, we profiled somatic mutations and their dynamics using next generation sequencing on serial samples from a total of 124 patients, consisting of a 31 patient discovery cohort and 93 patients from two validation cohorts. Whole-exome analysis on the discovery cohort revealed that 29 of 31 patients carry mutations related to at least one of eight commonly mutated pathways in AML. Mutations in genes related to DNA methylation and splicing machinery were found in T-cell samples, which expand at the initial diagnosis of the myelodysplasia, suggesting their importance as early disease events. On the other hand, somatic variants associated with signaling pathways arise or their allelic burdens expand significantly during progression. Our results indicate a strong association between mutations in activated signaling pathways and sAML progression. Overall, we demonstrate that distinct categories of genetic lesions play roles at different stages of sAML in a generally fixed order.
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This study was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT and Future Planning (NRF-2015R1A2A1A10054579) and the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT and Future Planning (NRF-2011-0030034). The biospecimens and data used for this study were provided by the Biobank of Chonnam National University Hwasun Hospital, a member of the Korea Biobank Network. TK is supported by the Queen Elizabeth II Graduate Scholarship for Science and Technology (University of Toronto) and the scholarship from Natural Science and Engineering Research Council of Canada (NSERC-PGS D2). We thank Dr Aaron Schimmer and Dr Meong Hi Son for their insightful discussions and advice on the manuscript. In addition, they would like to thank the reviewers for their valuable comments and suggestions.
TK, HK, ZZ and DK designed the study and its concept. HP, SHC, JA, YK, DY, JL, SJ, SYK, YHM, JC, SKS and JHM collected the samples and performed experiments. YK, MST, MC, ML and ZZ analyzed the sequencing data. TK, MST, ZZ and DK performed all downstream and statistical analyses. TK, MST, HK, ZZ and DK wrote the manuscript.
The authors declare no conflict of interest.
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Kim, T., Tyndel, M., Kim, H. et al. The clonal origins of leukemic progression of myelodysplasia. Leukemia 31, 1928–1935 (2017). https://doi.org/10.1038/leu.2017.17
Screening for myeloid mutations in patients with myelodysplastic syndromes and AML with myelodysplasia-related changes
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