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

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

Satoshi Wakita  1 , Atsushi Marumo  1 , Kaoru Morita  2 , Shinichi Kako  3 , Takashi Toya  4 , Yuho Najima  4 , Noriko Doki  4 , Junya Kanda  5 , Junya Kuroda  6 , Shinichiro Mori  7 , Atsushi Satake  8 , Kensuke Usuki  9 , Toshimitsu Ueki  10 , Nobuhiko Uoshima  11 , Yutaka Kobayashi  11 , Eri Kawata  12 , Kazutaka Nakayama  13 , Yuhei Nagao  14 , Katsuhiro Shono  14 , Motoharu Shibusawa  15 , Jiro Tadokoro  15 , Masao Hagihara  16 , Hitoji Uchiyama  17 , Naoyuki Uchida  18 , Yasushi Kubota  19 , Shinya Kimura  19 , Hisao Nagoshi  20 , Tatsuo Ichinohe  20 , Saiko Kurosawa  21 , Sayuri Motomura  22 , Akiko Hashimoto  23 , Hideharu Muto  24 , Eriko Sato  25 , Masao Ogata  26 , Kenjiro Mitsuhashi  27 , Jun Ando  28 , Haruko Tashiro  29 , Masahiro Sakaguchi  1 , Shunsuke Yui  1 , Kunihito Arai  1 , Tomoaki Kitano  1 , Miho Miyata  1 , Haruka Arai  1 , Masayuki Kanda  1 , Kako Itabashi  1 , Takahiro Fukuda  21 , Yoshinobu Kanda  2   3 , Hiroki Yamaguchi  1
Affiliations

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

Satoshi Wakita et al. Cancer Sci. 2023 Apr.

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 (DNMT3AR882 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 DNMT3AR882 mutations and the co-occurrence of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD), NPM1 mutations, and DNMT3AR882 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: DNMT3AR882 mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3AR882 mutations and triple mutations on prognosis and according to the classification of NPM1-mutated AML into three risk groups based on DNMT3AR882 /FLT3-ITD genotypes, we achieved the improved stratification of prognosis (p < 0.0001). We showed that DNMT3AR882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3AR882 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.

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Conflict of interest statement

No authors have a financial interest with respect to the conduction or reporting of the study. S. Kimura is an editorial board member of Cancer Science.

Figures

FIGURE 1
FIGURE 1
Effect of DNMT3A mutations on the prognosis of NPM1‐mutated acute myeloid leukemia (AML). (A) Kaplan–Meier plots (overall survival; OS) comparing DNMT3A genotype subgroups for all karyotypes/NPM1‐mutated AML. (B) Kaplan–Meier plots (OS censored at allo‐HSCT) comparing DNMT3A genotype subgroups for all karyotypes/NPM1‐mutated AML. (C) Kaplan–Meier plots (event‐free survival; EFS) comparing DNMT3A genotype subgroups for all karyotypes/NPM1‐mutated AML. (D) Kaplan–Meier plots (OS) comparing DNMT3A genotype subgroups for normal karyotype (NK)/NPM1‐mutated AML. (E) Kaplan–Meier plots (OS censored at allo‐HSCT) comparing DNMT3A genotype subgroups for NK/NPM1‐mutated AML. (F) Kaplan–Meier plots (EFS) comparing DNMT3A genotype subgroups for NK/NPM1‐mutated AML
FIGURE 2
FIGURE 2
Effect of DNMT3A mutations on the prognosis of NPM1 wild‐type acute myeloid leukemia (AML). (A) Kaplan–Meier plots (overall survival; OS) comparing DNMT3A genotype subgroups for all karyotypes/NPM1 wild‐type AML. (B) Kaplan–Meier plots (OS censored at allo‐HSCT) comparing DNMT3A genotype subgroups for all karyotypes/NPM1 wild‐type AML. (C) Kaplan–Meier plots (event‐free survival; EFS) comparing DNMT3A genotype subgroups for all karyotypes/NPM1 wild‐type AML. (D) Kaplan–Meier plots (OS) comparing DNMT3A genotype subgroups for normal karyotype (NK)/NPM1 wild‐type AML. (E) Kaplan–Meier plots (OS censored at allo‐HSCT) comparing DNMT3A genotype subgroups for NK/NPM1 wild‐type AML. (F) Kaplan–Meier plots (EFS) comparing DNMT3A genotype subgroups for NK/NPM1 wild‐type AML
FIGURE 3
FIGURE 3
Effect of FLT3‐ITD allelic ratio on the prognosis of NPM1 mutation‐positive/DNMT3A R882 wild‐type acute myeloid leukemia (AML) and NPM1 mutation‐positive/DNMT3A R882 mutation‐positive AML. (A) Kaplan–Meier plots (overall survival; OS) comparing FLT3‐ITD subgroups for NPM1 mutation‐positive/DNMT3A R882 wild‐type patients. (B) Kaplan–Meier plots (OS censored at allo‐HSCT) comparing FLT3‐ITD subgroups for NPM1 mutation‐positive/DNMT3AR882 wild‐type patients. (C) Kaplan–Meier plots (event‐free survival; EFS) comparing FLT3‐ITD subgroups for NPM1 mutation‐positive/DNMT3AR882 wild‐type patients. (D) Kaplan–Meier plots (OS) comparing FLT3‐ITD subgroups for NPM1 mutation‐positive/DNMT3AR882 mutation‐positive patients. (E) Kaplan–Meier plots (OS censored at allo‐HSCT) comparing FLT3‐ITD subgroups for NPM1 mutation‐positive/DNMT3AR882 mutation‐positive patients. (F) Kaplan–Meier plots (EFS) comparing FLT3‐ITD subgroups for NPM1 mutation‐positive/DNMT3AR882 mutation‐positive patients
FIGURE 4
FIGURE 4
Prognostic model based on DNMT3A R882 mutation/NPM1 mutation/FLT3‐ITD allelic ratio genotypes. (A) Prognostic stratification using NPM1/FLT3‐ITD genotypes (overall survival; OS) according to the European LeukemiaNet 2017 (ELN 2017) classification of NPM1‐mutated acute myeloid leukemia (AML). (B) Prognostic stratification using NPM1/FLT3‐ITD genotypes (OS censored at allo‐HSCT) according to the ELN 2017 classification of NPM1‐mutated AML. (C) Prognostic stratification using NPM1/FLT3‐ITD genotypes (event‐free survival; EFS) according to the ELN 2017 classification of NPM1‐mutated AML. (D) Prognostic stratification using DNMT3AR882/NPM1/FLT3‐ITD genotypes (OS) according to the multicenter collaborative program for gene sequencing of Japanese AML (GS‐JAML) classification of NPM1‐mutated AML. (E) Prognostic stratification using DNMT3AR882/NPM1/FLT3‐ITD genotypes (OS censored at allo‐HSCT) according to the GS‐JAML classification of NPM1‐mutated AML (F) Prognostic stratification using DNMT3AR882/NPM1/FLT3‐ITD genotypes (EFS) according to the GS‐JAML classification of NPM1‐mutated AML
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