CEBPA
Primary Author(s)*
Gordana Raca, MD, PhD, FACMG and Brian Davis PhD
Synonyms
CCAAT/Enhancer Binding Protein Alpha; CCAAT/Enhancer Binding Protein (C/EBP) Alpha; CEBP; C/EBP-Alpha
Genomic Location
Cytoband: 19q13.11
Genomic Coordinates:
chr19:33,299,934-33,302,564(GRCh38/hg38)
chr19:33,790,840-33,793,430 [hg19]
Cancer Category/Type
Acute Myeloid Leukemia (AML) with Biallelic Mutations of CEBPA - see Common Mutation Types below for more information.
--- Myeloid Neoplasms with Germline CEBPA Mutation
Gene Overview
CEBPA is an intronless gene encoding a transcription factor that contains a basic leucine zipper (bZIP) domain and recognizes the CCAAT motif in the promoters of target genes. The CEBPA-encoded protein functions in homodimers and also heterodimers with CCAAT/enhancer-binding proteins beta and gamma to modulate the expression of genes involved in cell cycle regulation. It coordinates proliferation arrest and the differentiation of myeloid progenitors, adipocytes, hepatocytes, and cells of the lung and the placenta. It is essential for the transition from common myeloid progenitors (CMP) to granulocyte/monocyte progenitors (GMP) [3].
Common Alteration Types
- Bi-allelic CEBPA mutations define a specific entity in the 2016 WHO classification of hematologic neoplasms [1]. AML cases with only one CEBPA mutation have different biologic and clinical characteristics and should not be classified into this category.
- AML with bi-allelic CEBPA mutations typically presents de novo; it accounts for approximately 4-9% of AML cases in children and young adults, and appears to be less common in older patients.
- Morphologically it meets the criteria for AML with or without maturation and more rarely may show myelomonocitic or monoblastic features. There are no any distinctive morphologic or immunophenotypic characteristics.
- More than 70% of the cases have a normal karyotype. The remaining cases may show del(9q) or different non-specific chromosome abnormalities.
- The bi-allelic CEBPA mutation is associated with a specific gene expression profile in leukemia clones, that is not seen in cases with a single CEBPA mutation. FLT3-ITD mutation is observed in 5-9% of the cases, while GATA2 zing-finger 1 mutation occurs in 39% of the patients. Importantly, all patients with bi-allelic CEBPA mutations have to be evaluted for the germline mutation status, to exclude germline inheritance of one of the alleles. Germline mutations in one copy of the CEBPA gene are associated with a familial AML syndrome which typically manifests as development of leukemia in childhood or adolescence (median age 24.5 years) in the absence of preceding abnormal blood counts or other clinical phenotypes. In AML with germline CEBPA mutation, the first mutation is germline and commonly occurs in the 5' end of the gene. The second mutation occurs as a somatic change in leukemia cells and typically localizes within the 3' end of the gene. The disorder appears to have near-complete penetrance for development of AML. AML with germline CEBPA mutation is associated with a favorable prognosis, with the survival rate reported in one study as 67% [2]. However, patients frequently experience recurrence, which at least in a subset of cases may in fact represent development of a novel independent clone with bi-allelic mutation rather than a true relapse.
- Sporadic cases of AML with bi-allelic CEBPA mutations are also associated with a favorable prognosis, similar to that of inv(16) or t(8;21) AML. The influence of FLT3-ITD and GATA2 mutations on prognosis of AML with bi-allelic CEBPA mutations is presently unclear.
| Copy Number Loss | Copy Number Gain | LOH | Loss-of-Function Mutation | Gain-of-Function Mutation | Translocation/Fusion |
|---|---|---|---|---|---|
| X |
Internal Pages
Acute Myeloid Leukemia (AML) with Biallelic Mutations of CEBPA
Myeloid Neoplasms with Germline CEBPA Mutation
External Links
CEBPA by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information
CEBPA by COSMIC - sequence information, expression, catalogue of mutations
CEBPA by CIViC - general knowledge and evidence-based variant specific information
CEBPA by St. Jude ProteinPaint mutational landscape and matched expression data.
CEBPA by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs
CEBPA by Cancer Index - gene, pathway, publication information matched to cancer type
CEBPA by OncoKB - mutational landscape, mutation effect, variant classification
CEBPA by My Cancer Genome - brief gene overview
CEBPA by UniProt - protein and molecular structure and function
CEBPA by Pfam - gene and protein structure and function information
CEBPA by GeneCards - general gene information and summaries
CEBPA by NCBI Gene - general gene information and summaries
References
1. Swerdlow SH et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th Edition, Volume 2, IARC Press: Lyon 2017, p. 142-144, p. 124-126.
2. Tawana K, et al., (2015) Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood 126(10):1214-23, PMID 26162409.
3. Avellino R.and Delwel R. (2017). Expression and regulation of C/EBPα in normal myelopoiesis and in malignant transformation. Blood 129: 2083-2091. PMID 28179278 DOI: 10.1182/blood-2016-09-687822
Notes
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