Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia

Mutations of CCAAT/enhancer–binding protein alpha (CEBPAmu) are found in 10% to 15% of de novo acute myeloid leukemia (AML) cases. Double-mutated CEBPA (CEBPAdm) is associated with a favorable prognosis; however, single-mutated CEBPA (CEBPAsm) does not seem to improve prognosis. We investigated CEBP...

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Published in:	Blood advances Vol. 6; no. 1; pp. 238 - 247
Main Authors:	Wakita, Satoshi, Sakaguchi, Masahiro, Oh, Iekuni, Kako, Shinichi, Toya, Takashi, Najima, Yuho, Doki, Noriko, Kanda, Junya, Kuroda, Junya, Mori, Shinichiro, Satake, Atsushi, Usuki, Kensuke, Ueki, Toshimitsu, Uoshima, Nobuhiko, Kobayashi, Yutaka, Kawata, Eri, Tajika, Kenji, Nagao, Yuhei, Shono, Katsuhiro, Shibusawa, Motoharu, Tadokoro, Jiro, Kayamori, Kensuke, Hagihara, Masao, Uchiyama, Hitoji, Uchida, Naoyuki, Kubota, Yasushi, Kimura, Shinya, Nagoshi, Hisao, Ichinohe, Tatsuo, Kurosawa, Saiko, Motomura, Sayuri, Hashimoto, Akiko, Muto, Hideharu, Sato, Eriko, Ogata, Masao, Mitsuhashi, Kenjiro, Ando, Jun, Marumo, Atsushi, Omori, Ikuko, Fujiwara, Yusuke, Terada, Kazuki, Yui, Shunsuke, Arai, Kunihito, Kitano, Tomoaki, Miyata, Miho, Kurosawa, Akiyo, Mizoguchi, Ayumi, Komatsu, Norio, Fukuda, Takahiro, Ohashi, Kazuteru, Kanda, Yoshinobu, Inokuchi, Koiti, Yamaguchi, Hiroki
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 11-01-2022 American Society of Hematology
Subjects:	Aged CCAAT-Enhancer-Binding Protein-alpha - genetics CCAAT-Enhancer-Binding Proteins - genetics Humans Karyotype Leukemia, Myeloid, Acute - diagnosis Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - metabolism Mutation Myeloid Neoplasia Prognosis
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Summary:	Mutations of CCAAT/enhancer–binding protein alpha (CEBPAmu) are found in 10% to 15% of de novo acute myeloid leukemia (AML) cases. Double-mutated CEBPA (CEBPAdm) is associated with a favorable prognosis; however, single-mutated CEBPA (CEBPAsm) does not seem to improve prognosis. We investigated CEBPAmu for prognosis in 1028 patients with AML, registered in the Multi-center Collaborative Program for Gene Sequencing of Japanese AML. It was found that CEBPAmu in the basic leucine zipper domain (bZIP) was strongly associated with a favorable prognosis, but CEBPAmu out of the bZIP domain was not. The presence of CEBPAmu in bZIP was a strong indicator of a higher chance of achieving complete remission (P < .001), better overall survival (OS; P < .001) and a lower risk of relapse (P < .001). The prognostic significance of CEBPAmu in bZIP was also observed in the subgroup with CEBPAsm (all patients: OS, P = .008; the cumulative incidence of relapse, P = .063; patients aged ≤70 years and with intermediate-risk karyotype: OS, P = .008; cumulative incidence of relapse, P = .026). Multivariate analysis of 744 patients aged ≤70 years showed that CEBPAmu in bZIP was the most potent predictor of OS (hazard ratio, 0.3287; P < .001). CEBPAdm was validated as a cofounding factor, which was overlapping with CEBPAmu in bZIP. In summary, these findings indicate that CEBPAmu in bZIP is a potent marker for AML prognosis. It holds potential in the refinement of treatment stratification and the development of targeted therapeutic approaches in CEBPA-mutated AML. •CEBPA mutation in the bZIP domain is associated with favorable prognosis in de novo AML, even if it was detected as CEBPAsm. [Display omitted]
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 S.W. and M.S. contributed equally to this study. Requests for data sharing may be submitted to Hiroki Yamaguchi (y-hiroki@fd6.so-net.ne.jp).
ISSN:	2473-9529 2473-9537
DOI:	10.1182/bloodadvances.2021004292