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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  IDH2 R140 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.

Frequency and Prognostic Impact of CEBPA Proximal, Distal and Core Promoter Methylation in Normal Karyotype AML: A Study on 623 Cases