Abstract
The clinical impact of aberrant CEBPA promoter methylation (PM) in AML is controversially discussed. The aim of this study was to clarify the significance of aberrant CEBPA PM with regard to clinical features in a cohort of 623 cytogenetically normal (CN) de novo AML. 555 cases had wild-type CEBPA, 68 cases harbored CEBPA mutations. The distal promoter was methylated in 238/623 cases (38.2%), the core promoter in 8 of 326 cases (2.5%), whereas proximal PM was never detected. CEBPA PM and CEBPA mutations were mutually exclusive. CEBPA distal PM positive cases were characterized by reduced CEBPA mRNA expression levels and elevated white blood cell counts. CEBPA distal PM was less frequent in patients with mutations in FLT3, NPM1 and TET2 and more frequent in cases with RUNX1 and IDH2R140 mutations. Overall, no association of methylation to prognosis was seen. However CEBPA distal PM was associated with inferior outcome in cases with low FLT3-ITD ratio or TET2 mutations. A distinct gene expression profile of CEBPA distal PM positive cases compared to CEBPA mutated and CEBPA distal PM negative cases was observed. In conclusion, the presence of aberrant CEBPA PM is associated with distinct biological features but impact on outcome is weak.
Highlights
The CCAAT/enhancer binding protein a (CEBPA) is a transcription factor with critical roles in tissue specific gene expression and proliferation arrest
We investigated the frequency and the clinical relevance of CEBPA promoter methylation (PM) in 623 de novo cytogenetically normal (CN)-AML and showed that aberrant DNA methylation in the promoter of CEBPA is very heterogeneously spread across the core, proximal and distal promoter regions
A distinct pattern of aberrant DNA methylation was mainly restricted to the distal promoter region of CEBPA (42.9%), whereas methylation of the CEBPA core promoter seems to be a rare event in AML (2.5%)
Summary
The CCAAT/enhancer binding protein a (CEBPA) is a transcription factor with critical roles in tissue specific gene expression and proliferation arrest. CEBPA expression is restricted to myelomonocytic cells and is up-regulated during granulocyte differentiation [1]. Mutations in the CEBPA gene have been described for approximately 5–10% of all AML patients and are most common in CN-AML (15%) [2,3]. In addition to genetic mutations, in recent years, epigenetic modifications, such as DNA promoter hypermethylation have gained increasing interest as additional mechanisms for transcriptional regulation of cancer-related genes. Inactivation of gene expression by abnormal hypermethylation of CpG islands in promoter regions of tumor suppressor genes has been described for many cancer entities [4]
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