Mutational analysis of DNMT3A improves the prognostic stratification of patients with acute myeloid leukemia期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

Mutational analysis of DNMT3A improves the prognostic stratification of patients with acute myeloid leukemia

Authors:	Satoshi Wakita Atsushi Marumo Kaoru Morita Shinichi Kako Takashi Toya Yuho Najima Noriko Doki Junya Kanda Junya Kuroda Shinichiro Mori Atsushi Satake Kensuke Usuki Toshimitsu Ueki Nobuhiko Uoshima Yutaka Kobayashi Eri Kawata Kazutaka Nakayama Yuhei Nagao Katsuhiro Shono Motoharu Shibusawa Jiro Tadokoro Masao Hagihara Hitoji Uchiyama Naoyuki Uchida Yasushi Kubota Shinya Kimura Hisao Nagoshi Tatsuo Ichinohe Saiko Kurosawa Sayuri Motomura Akiko Hashimoto Hideharu Muto Eriko Sato Masao Ogata Kenjiro Mitsuhashi Jun Ando Haruko Tashiro Masahiro Sakaguchi Shunsuke Yui Kunihito Arai Tomoaki Kitano Miho Miyata Haruka Arai Masayuki Kanda Kako Itabashi Takahiro Fukuda Yoshinobu Kanda Hiroki Yamaguchi

Affiliation:	1. Department of Hematology, Nippon Medical School, Tokyo, Japan;2. Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan;3. Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan;4. Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan;5. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;6. Division of Hematology and Oncology, Kyoto Prefectural University of Medicine, Kyoto, Japan;7. Hematology Department, St. Luke's International Hospital, Tokyo, Japan;8. First Department of Internal Medicine, Kansai Medical University, Osaka, Japan;9. Department of Hematology, NTT Medical Center Tokyo, Tokyo, Japan;10. Department of Hematology, Nagano Red Cross Hospital, Nagano, Japan;11. Department of Hematology, Japanese Red Cross, Kyoto Daini Hospital, Kyoto, Japan;12. Department of Hematology, Panasonic Health Insurance Organization Matsushita Memorial Hospital, Osaka, Japan;13. Department of Hematology, Yokohama Minami Kyousai Hospital, Yokohama-shi, Japan;14. Department of Hematology, Chiba Aoba Municipal Hospital, Chiba, Japan;15. Department of Hematology, IMS group Shinmatsudo Central General Hospital, Chiba, Japan;16. Department of Hematology, Eiju General Hospital, Tokyo, Japan;17. Department of Hematology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan;18. Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations, Toranomon Hospital, Tokyo, Japan;19. Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan;20. Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan;21. Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan;22. Department of Hematology, Tama-Hokubu Medical Center, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo, Japan;23. Department of Immunology and Hematology, Kobe City Nishi-Kobe Medical Center, Kobe, Japan;24. Division of Hematology Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan;25. Department of Hematology, Juntendo University Nerima Hospital, Tokyo, Japan;26. Department of Hematology, Oita University Hospital, Oita, Japan;27. Department of Hematology, Saitama Red Cross Hospital, Saitama, Japan;28. Division of Hematology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan;29. Department of Hematology/Oncology, Teikyo University School of Medicine, Tokyo, Japan;30. Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan

Abstract:	Nucleophosmin1 (NPM1) mutations are the most frequently detected gene mutations in acute myeloid leukemia (AML) and are considered a favorable prognostic factor. We retrospectively analyzed the prognosis of 605 Japanese patients with de novo AML, including 174 patients with NPM1-mutated AML. Although patients with NPM1-mutated AML showed a high remission rate, this was not a favorable prognostic factor for overall survival (OS); this is contrary to generally accepted guidelines. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNA methyltransferase 3A (DNMT3A^R882 mutations) were a strong predicative factor indicating poor prognosis in all AML (p < 0.0001) and NPM1-mutated AML cases (p = 0.0020). Furthermore, multivariate analysis of all AML cases showed that DNMT3A^R882 mutations and the co-occurrence of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD), NPM1 mutations, and DNMT3A^R882 mutations (triple mutations) were independent factors predicting a poor prognosis related to OS, with NPM1 mutations being an independent factor for a favorable prognosis (hazard ratios: DNMT3A^R882 mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3A^R882 mutations and triple mutations on prognosis and according to the classification of NPM1-mutated AML into three risk groups based on DNMT3A^R882/FLT3-ITD genotypes, we achieved the improved stratification of prognosis (p < 0.0001). We showed that DNMT3A^R882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3A^R882 mutations were excluded, NPM1 mutations were a favorable prognostic factor. This revealed that ethnological prognostic discrepancies in NPM1 mutations might be corrected through prognostic stratification based on the DNMT3A status.

Keywords:	acute myeloid leukemia DNMT3A NPM1 prognostic factor triple mutation

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