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. 2022 Jan 11;6(1):238-247.
doi: 10.1182/bloodadvances.2021004292.

Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia

Satoshi Wakita  1 , Masahiro Sakaguchi  1 , Iekuni Oh  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 , Kenji Tajika  13 , Yuhei Nagao  14 , Katsuhiro Shono  14 , Motoharu Shibusawa  15 , Jiro Tadokoro  15 , Kensuke Kayamori  16 , Masao Hagihara  17 , Hitoji Uchiyama  18 , Naoyuki Uchida  19 , Yasushi Kubota  20 , Shinya Kimura  20 , Hisao Nagoshi  21 , Tatsuo Ichinohe  21 , Saiko Kurosawa  22 , Sayuri Motomura  23 , Akiko Hashimoto  24 , Hideharu Muto  25 , Eriko Sato  26 , Masao Ogata  27 , Kenjiro Mitsuhashi  28 , Jun Ando  29 , Atsushi Marumo  1 , Ikuko Omori  1 , Yusuke Fujiwara  1 , Kazuki Terada  1 , Shunsuke Yui  1 , Kunihito Arai  1 , Tomoaki Kitano  1 , Miho Miyata  1 , Akiyo Kurosawa  1 , Ayumi Mizoguchi  1 , Norio Komatsu  29 , Takahiro Fukuda  22 , Kazuteru Ohashi  4 , Yoshinobu Kanda  2   3 , Koiti Inokuchi  1 , Hiroki Yamaguchi  1
Affiliations

Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia

Satoshi Wakita et al. Blood Adv. .

Abstract

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.

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Figures

None
Graphical abstract
Figure 1.
Figure 1.
Summary of CEBPA mutations in the primary cohort. (A) Distribution of CEBPA mutations. (B) Overlapping pattern of CEBPA mutations
Figure 2.
Figure 2.
Kaplan-Meier survival curves for OS and CIR comparing patients without CEBPAmu in bZIP and patients with CEBPAmu in bZIP. Analyses were conducted for 962 of 1028 patients who were followed up. Kaplan-Meier curves were stratified according to whether patients with AML have the CEBPA mutation in the bZIP domain: with CEBPAmu in bZIP (red), without CEBPAmu in bZIP (blue). Kaplan-Meier curve of OS for all patients (A), Kaplan-Meier curve of CIR for all patients (B), Kaplan-Meier curve of OS for patients aged ≤70 years and with intermediate-risk karyotype (C), and Kaplan-Meier curve of CIR for patients aged ≤70 years and with intermediate-risk karyotype (D).
Figure 3.
Figure 3.
Kaplan-Meier survival curves for OS and CIR of patients with CEBPAsm comparing CEBPAsm in bZIP and CEBPAsm out-of bZIP. Analyses were performed for 54 of 59 patients with CEBPAsm AML who were followed up. Kaplan-Meier curves were stratified according to whether CEBPA mutation was “in” or “out-of” the bZIP domain: red, CEBPAmu in bZIP; blue, CEBPAmu out-of bZIP. (A) Kaplan-Meier curve of OS for all patients (A), Kaplan-Meier curve of CIR for all patients (B), Kaplan-Meier curve of OS for patients aged ≤70 years and with intermediate-risk karyotype (C), and Kaplan-Meier curve of CIR for patients aged ≤70 years and with intermediate-risk karyotype (D).
Figure 4.
Figure 4.
The spectrum of concurrent mutations among different genes. (A) The overview of individual somatic mutations detected in AML with CEBPAmu. Columns represent patients with CEBPA mutations (66 patients with CEBPAdm and 41 patients with CEBPAsm), and rows represent the genotypes. (B) Correlation matrix based on the Pearson correlation coefficient analyses. The Pearson product-moment correlation coefficients were calculated, and correlation matrices were constructed for 107 patients with AML with CEBPAmu. Different colors are used to represent different correlation strengths. The color scale is defined by the color bar legend. Here, the red color suggests a strong positive correlation, whereas the blue color indicates a strong negative correlation. The underline represents the P value <.05.
Figure 5.
Figure 5.
Kaplan-Meier survival curves for OS of patients with CEBPAmu in bZIP comparing the 3 genotypes (GATA2 positive/WT1 negative, GATA2 negative/WT1 positive, GATA2 negative/WT1 negative). Kaplan-Meier curves were stratified according to the 3 genotypes: red, GATA2 positive/WT1 negative; blue, GATA2 negative/WT1 positive; and gray, GATA2 negative/WT1 negative. There was no genotype of GATA2 positive/WT1 positive. (A) Kaplan-Meier curve of OS for all patients (among the 3 groups P = .410; GATA2 positive/WT1 negative vs GATA2 negative/WT1 positive, P = .154; GATA2 negative/WT1 positive vs GATA2 negative/WT1 negative, P = .483; GATA2 positive/WT1 negative vs GATA2 negative/WT1 negative, P = .366). (B) Kaplan-Meier curve of OS for patients aged ≤70 years and with intermediate-risk karyotype (among the 3 groups, P = .072; GATA2 positive/WT1 negative vs GATA2 negative/WT1 positive, P = .016; GATA2 negative/WT1 positive vs GATA2 negative/WT1 negative, P = .208; GATA2 positive/WT1 negative vs GATA2 negative/WT1 negative, P = .113).
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References

    1. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136-1152. - PubMed
    1. Döhner H, Estey E, Grimwade D, et al. . Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447. - PMC - PubMed
    1. Kurosawa S, Yakushijin K, Yamaguchi T, et al. . Changes in incidence and causes of non-relapse mortality after allogeneic hematopoietic cell transplantation in patients with acute leukemia/myelodysplastic syndrome: an analysis of the Japan Transplant Outcome Registry. Bone Marrow Transplant. 2013;48(4):529-536. - PubMed
    1. Wouters BJ, Löwenberg B, Erpelinck-Verschueren CA, van Putten WL, Valk PJ, Delwel R. Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood. 2009;113(13):3088-3091. - PMC - PubMed
    1. Pabst T, Eyholzer M, Fos J, Mueller BU. Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favourable prognosis. Br J Cancer. 2009;100(8):1343-1346. - PMC - PubMed

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