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

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

doi:10.1111/cas.15720

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

Cancer Sci. 2023 Apr;114(4):1297-1308. doi: 10.1111/cas.15720. Epub 2023 Jan 27.

Authors

Satoshi Wakita¹, Atsushi Marumo¹, Kaoru Morita², Shinichi Kako³, Takashi Toya⁴, Yuho Najima⁴, Noriko Doki⁴, Junya Kanda⁵, Junya Kuroda⁶, Shinichiro Mori⁷, Atsushi Satake⁸, Kensuke Usuki⁹, Toshimitsu Ueki¹⁰, Nobuhiko Uoshima¹¹, Yutaka Kobayashi¹¹, Eri Kawata¹², Kazutaka Nakayama¹³, Yuhei Nagao¹⁴, Katsuhiro Shono¹⁴, Motoharu Shibusawa¹⁵, Jiro Tadokoro¹⁵, Masao Hagihara¹⁶, Hitoji Uchiyama¹⁷, Naoyuki Uchida¹⁸, Yasushi Kubota¹⁹, Shinya Kimura¹⁹, Hisao Nagoshi²⁰, Tatsuo Ichinohe²⁰, Saiko Kurosawa²¹, Sayuri Motomura²², Akiko Hashimoto²³, Hideharu Muto²⁴, Eriko Sato²⁵, Masao Ogata²⁶, Kenjiro Mitsuhashi²⁷, Jun Ando²⁸, Haruko Tashiro²⁹, Masahiro Sakaguchi¹, Shunsuke Yui¹, Kunihito Arai¹, Tomoaki Kitano¹, Miho Miyata¹, Haruka Arai¹, Masayuki Kanda¹, Kako Itabashi¹, Takahiro Fukuda²¹, Yoshinobu Kanda^{2

3}, Hiroki Yamaguchi¹

Affiliations

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.

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: DNMT3A; NPM1; acute myeloid leukemia; prognostic factor; triple mutation.

MeSH terms

DNA (Cytosine-5-)-Methyltransferases* / genetics
DNA Mutational Analysis
Humans
Leukemia, Myeloid, Acute* / genetics
Mutation
Nucleophosmin / genetics
Prognosis
Retrospective Studies

Substances

DNA (Cytosine-5-)-Methyltransferases
Nucleophosmin
DNMT3A protein, human
NPM1 protein, human