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

被引：15

作者：

Wakita, Satoshi ^{[1
]}

Marumo, Atsushi ^{[1
]}

Morita, Kaoru ^{[2
]}

Kako, Shinichi ^{[3
]}

Toya, Takashi ^{[4
]}

Najima, Yuho ^{[4
]}

Doki, Noriko ^{[4
]}

Kanda, Junya ^{[5
]}

Kuroda, Junya ^{[6
]}

Mori, Shinichiro ^{[7
]}

Satake, Atsushi ^{[8
]}

Usuki, Kensuke ^{[9
]}

Ueki, Toshimitsu ^{[10
]}

Uoshima, Nobuhiko ^{[11
]}

Kobayashi, Yutaka ^{[11
]}

Kawata, Eri ^{[12
]}

Nakayama, Kazutaka ^{[13
]}

Nagao, Yuhei ^{[14
]}

Shono, Katsuhiro ^{[14
]}

Shibusawa, Motoharu ^{[15
]}

Tadokoro, Jiro ^{[15
]}

Hagihara, Masao ^{[16
]}

Uchiyama, Hitoji ^{[17
]}

Uchida, Naoyuki ^{[18
]}

Kubota, Yasushi ^{[19
]}

Kimura, Shinya ^{[19
]}

Nagoshi, Hisao ^{[20
]}

Ichinohe, Tatsuo ^{[20
]}

Kurosawa, Saiko ^{[21
]}

Motomura, Sayuri ^{[22
]}

Hashimoto, Akiko ^{[23
]}

Muto, Hideharu ^{[24
]}

Sato, Eriko ^{[25
]}

Ogata, Masao ^{[26
]}

Mitsuhashi, Kenjiro ^{[27
]}

Ando, Jun ^{[28
]}

Tashiro, Haruko ^{[29
]}

Sakaguchi, Masahiro ^{[1
]}

Yui, Shunsuke ^{[1
]}

Arai, Kunihito ^{[1
]}

Kitano, Tomoaki ^{[1
]}

Miyata, Miho ^{[1
]}

Arai, Haruka ^{[1
]}

Kanda, Masayuki ^{[1
]}

Itabashi, Kako ^{[1
]}

Fukuda, Takahiro ^{[21
]}

Kanda, Yoshinobu ^{[2
,3
]}

Yamaguchi, Hiroki ^{[1
]}

机构：

[1] Nippon Med Sch, Dept Hematol, 1-1-5 Sendagi,Bunkyo Ku, Tokyo 1138603, Japan

[2] Jichi Med Univ, Dept Med, Div Hematol, Shimotsuke, Tochigi, Japan

[3] Jichi Med Univ, Div Hematol, Saitama Med Ctr, Saitama, Japan

[4] Komagome Hosp, Tokyo Metropolitan Canc & Infect Dis Ctr, Hematol Div, Tokyo, Japan

[5] Kyoto Univ, Grad Sch Med, Dept Hematol & Oncol, Kyoto, Japan

[6] Kyoto Prefectural Univ Med, Div Hematol & Oncol, Kyoto, Japan

[7] St Lukes Int Hosp, Hematol Dept, Tokyo, Japan

[8] Kansai Med Univ, Dept Internal Med 1, Osaka, Japan

[9] NTT Med Ctr Tokyo, Dept Hematol, Tokyo, Japan

[10] Nagano Red Cross Hosp, Dept Hematol, Nagano, Japan

[11] Kyoto Daini Hosp, Dept Hematol, Japanese Red Cross, Kyoto, Japan

[12] Panasonic Hlth Insurance Org Matsushita Mem Hosp, Dept Hematol, Osaka, Japan

[13] Yokohama Minami Kyousai Hosp, Dept Hematol, Yokohama, Japan

[14] Chiba Aoba Municipal Hosp, Dept Hematol, Chiba, Japan

[15] IMS Grp Shinmatsudo Cent Gen Hosp, Dept Hematol, Chiba, Japan

[16] Eiju Gen Hosp, Dept Hematol, Tokyo, Japan

[17] Japanese Red Cross Kyoto Daiichi Hosp, Dept Hematol, Kyoto, Japan

[18] Toranomon Gen Hosp, Dept Hematol, Federat Natl Publ Serv Personnel Mutual Aid Assoc, Tokyo, Japan

[19] Saga Univ, Fac Med, Dept Internal Med, Div Hematol Resp Med & Oncol, Saga, Japan

[20] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Hematol & Oncol, Hiroshima, Japan

[21] Natl Canc Ctr, Dept Hematopoiet Stem Cell Transplantat, Tokyo, Japan

[22] Tokyo Metropolitan Hlth & Med Treatment Corp, Tama Hokubu Med Ctr, Dept Hematol, Tokyo, Japan

[23] Kobe City Nishi Kobe Med Ctr, Dept Immunol & Hematol, Kobe, Japan

[24] Tokyo Metropolitan Otsuka Hosp, Div Hematol, Tokyo, Japan

[25] Juntendo Univ, Dept Hematol, Nerima Hosp, Tokyo, Japan

[26] Oita Univ Hosp, Dept Hematol, Yufu, Oita, Japan

[27] Saitama Red Cross Hosp, Dept Hematol, Saitama, Japan

[28] Juntendo Univ, Dept Internal Med, Div Hematol, Sch Med, Tokyo, Japan

[29] Teikyo Univ, Dept Hematol Oncol, Sch Med, Tokyo, Japan

来源：

CANCER SCIENCE | 2023年 / 114卷 / 04期

关键词：

acute myeloid leukemia; DNMT3A; NPM1; prognostic factor; triple mutation; ACUTE MYELOGENOUS LEUKEMIA; NPM1; MUTATIONS; GENE-MUTATIONS; NUCLEOPHOSMIN; IMPACT; ADULTS; AML; DIAGNOSIS; FLT3-ITD;

D O I：

10.1111/cas.15720

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1297 / 1308

页数：12

共 31 条

[1] Prognostic Impact of Concurrent DNMT3A, FLT3 and NPM1 Gene Mutations in Acute Myeloid Leukemia Patients [J].

Abd Elrhman, Heba Allah E. ;

El-Meligui, Yomna M. ;

Elalawi, Saffaa M. .

CLINICAL LYMPHOMA MYELOMA & LEUKEMIA, 2021, 21 (12) :E960-E969

[2] DNMT3A R882 Mutation with FLT3-ITD Positivity Is an Extremely Poor Prognostic Factor in Patients with Normal-Karyotype Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation [J].

Ahn, Jae-Sook ;

Kim, Hyeoung-Joon ;

Kim, Yeo-Kyeoung ;

Lee, Seun-Shin ;

Jung, Sung-Hoon ;

Yang, Deok-Hwan ;

Lee, Je-Jung ;

Kim, Nan Young ;

Choi, Seung Hyun ;

Jung, Chul Won ;

Jang, Jun-Ho ;

Kim, Hee Je ;

Moon, Joon Ho ;

Sohn, Sang Kyun ;

Won, Jong-Ho ;

Kim, Sung-Hyun ;

Kim, Dennis Dong Hwan .

BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 2016, 22 (01) :61-70

[3] Co-occurrence of DNMT3A, NPM1, FLT3 mutations identifies a subset of acute myeloid leukemia with adverse prognosis [J].

Bezerra, Matheus F. ;

Lima, Aleide S. ;

Pique-Borras, Maria-Riera ;

Silveira, Douglas R. ;

Coelho-Silva, Juan L. ;

Pereira-Martins, Diego A. ;

Weinhauser, Isabel ;

Franca-Neto, Pedro L. ;

Quek, Lynn ;

Corby, Anna ;

Oliveira, Mayara M. ;

Lima, Marinus M. ;

de Assis, Reijane A. ;

Campos, Paula de Melo ;

Duarte, Bruno K. ;

Bendit, Israel ;

Rocha, Vanderson ;

Rego, Eduardo M. ;

Traina, Fabiola ;

Saad, Sara T. ;

Beltrao, Eduardo I. ;

Bezerra, Marcos A. ;

Lucena-Araujo, Antonio R. .

BLOOD, 2020, 135 (11) :870-875

[4] Nucleophosmin mutation in Southeast Asian acute myeloid leukemia:: eight novel variants, FLT3 coexistence and prognostic impact of NPM1/FLT3 mutations [J].

Boonthimat, Chetsada ;

Thongnoppakhun, Wanna ;

Auewarakul, Chirayu U. .

HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, 2008, 93 (10) :1565-1569

[5] Nucleophosmin mutations in De novo acute myeloid leukemia:: The age-dependent incidences and the stability during disease [J].

Chou, WC ;

Tang, JL ;

Lin, LI ;

Yao, M ;

Tsay, W ;

Chen, CY ;

Wu, SJ ;

Huang, CF ;

Chiou, RJ ;

Tseng, MH ;

Lin, DT ;

Lin, KH ;

Chen, YC ;

Tien, HF .

CANCER RESEARCH, 2006, 66 (06) :3310-3316

[6] Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN [J].

Doehner, Hartmut ;

Wei, Andrew H. ;

Appelbaum, Frederick R. ;

Craddock, Charles ;

DiNardo, Courtney D. ;

Dombret, Herve ;

Ebert, Benjamin L. ;

Fenaux, Pierre ;

Godley, Lucy A. ;

Hasserjian, Robert P. ;

Larson, Richard A. ;

Levine, Ross L. ;

Miyazaki, Yasushi ;

Niederwieser, Dietger ;

Ossenkoppele, Gert ;

Roellig, Christoph ;

Sierra, Jorge ;

Stein, Eytan M. ;

Tallman, Martin S. ;

Tien, Hwei-Fang ;

Wang, Jianxiang ;

Wierzbowska, Agnieszka ;

Lowenberg, Bob .

BLOOD, 2022, 140 (12) :1345-1377

[7] Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel [J].

Doehner, Hartmut ;

Estey, Elihu ;

Grimwade, David ;

Amadori, Sergio ;

Appelbaum, Frederick R. ;

Buechner, Thomas ;

Dombret, Herve ;

Ebert, Benjamin L. ;

Fenaux, Pierre ;

Larson, Richard A. ;

Levine, Ross L. ;

Lo-Coco, Francesco ;

Naoe, Tomoki ;

Niederwieser, Dietger ;

Ossenkoppele, Gert J. ;

Sanz, Miguel ;

Sierra, Jorge ;

Tallman, Martin S. ;

Tien, Hwei-Fang ;

Wei, Andrew H. ;

Lowenberg, Bob ;

Bloomfield, Clara D. .

BLOOD, 2017, 129 (04) :424-447

[8] Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics:: interaction with other gene mutations [J].

Döhner, K ;

Schlenk, RF ;

Habdank, M ;

Scholl, C ;

Rücker, FG ;

Corbacioglu, A ;

Bullinger, L ;

Fröhling, S ;

Döhner, H .

BLOOD, 2005, 106 (12) :3740-3746

[9] Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. [J].

Falini, B ;

Mecucci, C ;

Tiacci, E ;

Alcalay, M ;

Rosati, R ;

Pasqualucci, L ;

La Starza, R ;

Diverio, D ;

Colombo, E ;

Santucci, A ;

Bigerna, B ;

Pacini, R ;

Pucciarini, A ;

Liso, A ;

Vignetti, M ;

Fazi, P ;

Meani, N ;

Pettirossi, V ;

Saglio, G ;

Mandelli, F ;

Lo-Coco, F ;

Pelicci, P ;

Martelli, MF .

NEW ENGLAND JOURNAL OF MEDICINE, 2005, 352 (03) :254-266

[10] Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG) [J].

Gaidzik, Verena I. ;

Schlenk, Richard F. ;

Paschka, Peter ;

Stoelzle, Anja ;

Spaeth, Daniela ;

Kuendgen, Andrea ;

von Lilienfeld-Toal, Marie ;

Brugger, Wolfram ;

Derigs, Hans Guenter ;

Kremers, Stephan ;

Greil, Richard ;

Raghavachar, Aruna ;

Ringhoffer, Mark ;

Salih, Helmut R. ;

Wattad, Mohammed ;

Kirchen, Heinz G. ;

Runde, Volker ;

Heil, Gerhard ;

Petzer, Andreas L. ;

Girschikofsky, Michael ;

Heuser, Michael ;

Kayser, Sabine ;

Goehring, Gudrun ;

Teleanu, Maria-Veronica ;

Schlegelberger, Brigitte ;

Ganser, Arnold ;

Krauter, Juergen ;

Bullinger, Lars ;

Doehner, Hartmut ;

Doehner, Konstanze .

BLOOD, 2013, 121 (23) :4769-4777

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