Cancer Res Treat.  2023 Jul;55(3):1011-1022. 10.4143/crt.2022.1407.

Clinical Significance of bZIP In-Frame CEBPA-Mutated Normal Karyotype Acute Myeloid Leukemia

• Ahn SY
• Kim T
• Kim M
• Song GY
• Jung SH
• Yang DH
• Lee JJ
• Kim MY
• Jung CW
• Jang JH
• Kim HJ
• Moon JH
• Sohn SK
• Won JH
• Kim SH
• Kim HJ
• Ahn JS
• Kim DDH

• KMID: 2544181
• DOI: http://doi.org/10.4143/crt.2022.1407

Abstract

Purpose
We evaluated the characteristics of CCAAT/enhancer-binding protein α (CEBPA) mutations and the significance of a basic leucine zipper in-frame mutation (bZIP^in-f) of CEBPA in patients with acute myeloid leukemia with a normal karyotype.
Materials and Methods
Based on updated knowledge of CEBPA mutations, we conducted next-generation sequencing analyses in a previously established real-world cohort.
Results
Among 78 of a total of 395 patients (19.7%), 50 had bZIP^in-f CEBPA, and 28 had non-bZIP^in-f CEBPA. In the multivariate analysis, patients with NPM1^mut, those with bZIP^in-f CEBPA, and those who underwent allogeneic hematopoietic cell transplantation (allo-HCT) had favorable overall survival (OS), but FLT3-ITD^mut was a poor prognostic indicator. For relapse-free survival (RFS) and cumulative incidence of relapse, bZIP^in-f CEBPA, and allo-HCT were associated with favorable outcomes; FLT3-ITD^pos was associated with worse outcomes. In the CEBPA double-mutated group (CEBPA^dm), bZIP^in-f CEBPA was associated with superior outcomes in terms of OS (p=0.007) and RFS (p=0.007) compared with non-bZIP^in-f CEBPA. Of 50 patients with bZIP^in-f CEBPA, 36 patients had at least one mutation. When grouped by the presence of mutations in chromatic/DNA modifiers (C), cohesion complex (C), and splicing genes (S) (CCS mutations), CCS-mutated bZIP^in-f CEBPA was associated with poor OS (p=0.044; hazard ratio [HR], 2.419) and a trend in inferior RFS (p=0.186; HR, 1.838).
Conclusion
Only bZIP^in-f CEBPA was associated with favorable outcomes in patients with CEBPA^dm. However, some mutations accompanying bZIP^in-f CEBPA showed inferior OS; thus, further studies with larger numbers of patients are required for clear conclusions of the significance of bZIP^in-f CEBPA.

Keyword

Leukemia; Myeloid; Acute; Next-generation sequencing; Allogeneic transplantation

Figure

• 

  Fig. 1 Prevalence of genetic alterations in the samples obtained at diagnosis from patients with CEBPA-mutated normal karyotype acute myeloid leukemia (n=78). bZIPin-f CEBPA, bZIP in-frame CEBPA mutation; CEBPA, CCAAT/enhancer-binding protein α; non-bZIPin-f CEBPA, non bZIP or non-in-frame CEBPA mutation.

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  Fig. 2 Prognostic significance according to the CEBPA mutation status for all 395 patients with normal karyotype acute myeloid leukemia. OS (A), RFS (B), cumulative incidence of relapse (C), and non-relapse mortality (D). bZIPin-f CEBPA, bZIP in-frame CEBPA mutation; CEBPA, CCAAT/enhancer-binding protein α; CEBPAwild, CEBPA wild-type; non-bZIPin-f CEBPA, non bZIP or non-in-frame CEBPA mutation; OS, overall survival; RFS, relapse-free survival.

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  Fig. 3 Prognostic significance according to bZIPin-f or non-bZIPin-f CEBPA in patients with CEBPA double mutations. OS (A), RFS (B), cumulative incidence of relapse (C), and non-relapse mortality (D). bZIPin-f CEBPA, bZIP in-frame CEBPA mutation; CEBPA, CCAAT/enhancer-binding protein α; non-bZIPin-f CEBPA, non bZIP or non-in-frame CEBPA mutation; OS, overall survival; RFS, relapse-free survival.

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  Fig. 4 OS (A), RFS (B), cumulative incidence of relapse (C), and non-relapse mortality (D) by landmark analysis according to the type of consolidation therapy in patients with bZIPin-f CEBPA with normal karyotype acute myeloid leukemia. Allo-HCT, allogeneic hematopoietic cell transplantation; bZIPin-f CEBPA, bZIP in-frame CEBPA mutation; OS, overall survival; RFS, relapse-free survival.

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  Fig. 5 Prognostic significance by co-occurrence of mutations in patients with bZIPin-f CEBPA–mutated normal karyotype acute myeloid leukemia. OS (A), RFS (B), cumulative incidence of relapse (C), and non-relapse mortality (D). bZIPin-f CEBPA, bZIP in-frame CEBPA mutation; CEBPA, CCAAT/enhancer-binding protein α; CCSs mutations, mutations in chromatic/DNA modifiers (C), cohesion complex (C), and splicing genes (S).

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