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Acute Leukemias

Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients

Abstract

To clarify the cooperative roles of recurrently identified mutations and to establish a more precise risk classification system in acute myeloid leukemia (AML), we comprehensively analyzed mutations in 51 genes, as well as cytogenetics and 11 chimeric transcripts, in 197 adult patients with de novo AML who were registered in the Japan Adult Leukemia Study Group AML201 study. We identified a total of 505 mutations in 44 genes, while only five genes, FLT3, NPM1, CEBPA, DNMT3A and KIT, were mutated in more than 10% of the patients. Although several cooperative and exclusive mutation patterns were observed, the accumulated mutation number was higher in cytogenetically normal AML and lower in AML with RUNX1-RUNX1T1 and CBFB-MYH11, indicating a strong potential of these translocations for the initiation of AML. Furthermore, we evaluated the prognostic impacts of each sole mutation and the combinations of mutations and/or cytogenetics, and demonstrated that AML patients could be clearly stratified into five risk groups for overall survival by including the mutation status of DNMT3A, MLL-PTD and TP53 genes in the risk classification system of the European LeukemiaNet. These results indicate that the prognosis of AML could be stratified by the major mutation status in combination with cytogenetics.

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Acknowledgements

This study was performed as a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct), Ministry of Education, Culture, Sports, Science and Technology of Japan, and was also supported by Grants-in-Aid from the Scientific Research Program from the Japanese Ministry of Education, Culture, Sports, Science, and Technology, the Ministry of Health, Labor and Welfare for Cancer Research (Clinical Cancer Research H23-004 and H25-006), the National Cancer Center Research and Development Fund (23-A-23) and from KAKENHI (22134006 and 23249052).

Author contributions

H Kiyoi, S Ogawa and TN designed the study, interpreted the data and wrote the manuscript; RK, YN, T Kato, EY, KS and FC performed molecular analysis and interpreted the data; YN, YS, KC, HT, SM and S Ogawa performed bioinformatics; NA, S Ohtake, SM, YM, TS, YO, N Usui, H Kanamori, T Kiguchi, KI, N Uike, FK, KK, CN, MO, AT, FI, HS, YK and HM collected samples and clinical data, contributed to the interpretation of the data and critically reviewed the draft; and all authors approved the final version submitted for the publication.

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Correspondence to H Kiyoi or S Ogawa.

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Competing interests

H Kiyoi: Research funding from Bristol-Myers Squibb, Novartis Pharma, Chugai Pharmaceutical Co., Ltd. and Kyowa Hakko Kirin Co., Ltd. YM: Honoraria from Bristol-Myers Squibb, Novartis Pharma, Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd. and Celgene Japan; Research funding from Bristol-Myers Squibb, Novartis Pharma, Chugai Pharmaceutical Co., Ltd. and Kyowa Hakko Kirin Co., Ltd. NU: Consultant for Kyowa Hakko Kirin Co., Ltd.; Honoraria from Bristol-Myers Squibb, Novartis Pharma and Chugai Pharmaceutical Co., Ltd.; Research funding from Bristol-Myers Squibb, Novartis Pharma, Chugai Pharmaceutical Co., Ltd. and Kyowa Hakko Kirin Co., Ltd. TN: Research funding from Bristol-Myers Squibb, Novartis Pharma, Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Dainippon Sumitomo Pharma and Zenyaku Kogyo. The other authors declare no conflict of interest.

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Kihara, R., Nagata, Y., Kiyoi, H. et al. Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. Leukemia 28, 1586–1595 (2014). https://doi.org/10.1038/leu.2014.55

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