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Familial Acute Myeloid Leukemia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The CCAAT/enhancer binding protein (C/EBP), alpha gene (CEBPA) is a single exon gene located on chromosome 19q13.1 band. The gene belongs to a family of basic leucine zipper proteins, and encodes for a transcription factor that is crucial for maturation of hematopoietic myeloid cells; no mature granulocytes are observed in CEBPA-mutant mice and the t(8;21) translocation downregulates CEBPA to lead to AML [35–37]. The CEBPA gene has 2 transactivation domains at the N-terminus, and a basic region and leucine zipper region at the C-terminus. Mutations in CEBPA may be present in sporadic AML in 5%–14% cases. Most commonly, mutations in the N-terminus cause a frameshift, leading to premature termination and absence of the normal, full-length 42 kDa protein, but still allowing downstream expression for formation of the smaller 30 kDa protein, a dominant-negative isoform. Mutations in the C-terminus disrupt the leucine zipper region, which prevents dimerization and loss of DNA activity [36].
Acute Myeloid Leukemia with Recurrent Genetic Abnormalities
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
The prognosis of AML with mutated CEBPA is favorable. The CEBPA gene is located on chromosome 19q31.1. CEBPA mutations are detected in 10% of AMLs. Morphologically and phenotypically, AMLs with CEBPA mutation resemble AML with or without maturation. Blasts often display an aberrant CD7 expression.
CEBPA mutants down-regulate AML cell susceptibility to NK-mediated lysis by disruption of the expression of NKG2D ligands, which can be restored by LSD1 inhibition
Published in OncoImmunology, 2022
Meng Liu, Mengbao Du, Jian Yu, Zijun Qian, Yang Gao, Wenjue Pan, Xiujie Zhao, Mowang Wang, Huimin Li, Jiaqi Zheng, Qianshuo Huang, Li-Mengmeng Wang, Haowen Xiao
The CEBPA transcripts are more susceptible to instability.1 Studies reported transcriptional deregulation of CEBPA either by DNA methylation or by the recruitment of transcriptional repressor complexes to regulatory elements in the CEBPA locus.18 Hypermethylation of the CEBPA promoter region has been reported to result in down-regulation of CEBPA expression in AML and to be as a prognostic biomarker.19–22 On the other hand, we proceeded on the basis of the reported results of the potential of hypomethylating agents (HMAs) to up-regulate NK-activating molecules, such as NKG2D ligands, on tumor cells through their epigenetic modulation, and thereby, sensitize tumors to NK-cell-mediated killing for different cancers including AML.23 Azacitidine/ 5-azacytidine (Vidaza, AZA) and decitabine/ 5-aza-29- deoxycytidine (Dacogen, DAC) are two HMAs currently used for the treatment of AML and myelodysplastic syndromes. We first evaluated the impacts of AZA and DAC on the expression of ULBPs in the AML cell lines. NB4 cells, a low endogenous C/EBPα-p42 and ULBP2/5/6 expressing cell line, were cultured in the presence or absence of AZA at 0.05 to 1 μM or DAC at 0.05 to 5 μM for 48 h. We demonstrated that DAC reactivated C/EBPα expression (Figure 5(a) and Supplementary Figure S2) and up-regulated the expression of ULBPs in the NB4 cells (Figure 5(b)). However, AZA had no significant effect on induction of the expression of ULBPs in the NB4 cells (Supplementary Figure S3).
Frequency and clinical impact of WT1 mutations in the context of CEBPA-mutated acute myeloid leukemia
Published in Hematology, 2022
Ting Wang, Haiying Hua, Zheng Wang, Biao Wang, Liujun Cao, Wei Qin, Pin Wu, Xiaohui Cai, Hongying Chao, XuZhang Lu
CCAAT/enhancer binding protein a (CEBPA) plays a crucial role in the repression of self-renewal, cell cycle arrest, and myeloid differentiation of mature neutrophils during normal hematopoiesis[1, 2]. Mutations in the CEBPA gene can occur across the whole coding region and have been described in approximately 6-24% of all acute myeloid leukemia (AML) patients[3–5]. CEBPA-mutated (CEBPAmut) patients can be subdivided into two different subgroups: (1) AML carrying one mutation on one allele (single-mutated CEBPA, CEBPAsm) and (2) AML with two CEBPA mutations (double-mutated CEBPA, CEBPAdm), typically showing an N-terminal mutation and a basic leucine zipper gene mutation. However, only patients who harbor CEBPA double mutations are associated with favorable outcomes[6, 7]. In the 2016 World Health Organization (WHO) classification of leukemia, AML with CEBPAdm was included as a distinctive disease entity due to its unique biological and clinical profiles[8].
Genetic profiling in acute myeloid leukemia: a path to predicting treatment outcome
Published in Expert Review of Hematology, 2018
Giuseppe Visani, Federica Loscocco, Alessandro Isidori, Pier Paolo Piccaluga
Subsequently, also AML cases presenting with NPM1 and CEBPA mutations were found to have distinct GEP [38,39]. NPM1-mutated AML molecular signature was characterized by activation of diverse members of the homeodomain-containing family of transcription factors, including the HOXA and HOXB genes [40]. In CEBPA-mutated AML with NK, only CEBPA double mutants, but not single mutants exhibited a characteristic GEP [41]. In addition, Wouters et al. identified a specific subgroup of patients with GEP resembling that of CEBPAmut-positive cases, although these patients did not carry the respective mutation. Grippingly, this subgroup was characterized by the epigenetic silencing of CEBPA expression through the hypermethylation of its promoter [42]. By contrast, FLT3 mutations usually represent a secondary event in leukemic cell evolution; therefore, it is more difficult to predict them by GEP, due to more prominent overlying driver genes related signatures.