A regulatory element in the 3′-untranslated region of CEBPA is associated with myeloid/NK/T-cell leukemia

Objectives CCAAT/enhancer-binding protein alpha (CEBPA) is an essential transcription factor for myeloid differentiation. Not only mutation of the CEBPA gene, but also promoter methylation, which results in silencing of CEBPA, contributes to the pathogenesis of acute myeloid leukemia (AML). We sought for another differentially methylated region (DMR) that associates with the CEBPA silencing and disease phenotype. Methods Using databases, we identified a conserved DMR in the CEBPA 3 '-untranslated region (UTR). Results Methylation-specific PCR analysis of 231 AML cases showed that hypermethylation of the 3 '-UTR was associated with AML that had a myeloid/NK/T-cell phenotype and downregulated CEBPA. Most of these cases were of an immature phenotype with CD7/CD56 positivity. These cases were significantly associated with lower hemoglobin levels than the others. Furthermore, we discovered that the CEBPA 3 '-UTR DMR can enhance transcription from the CEBPA native promoter. In vitro experiments identified IKZF1-binding sites in the 3 '-UTR that are responsible for this increased transcription of CEBPA. Conclusions These results indicate that the CEBPA 3 '-UTR DMR is a novel regulatory element of CEBPA related to myeloid/NK/T-cell lineage leukemogenesis. Transcriptional regulation of CEBPA by IKZF1 may provide a clue for understanding the fate determination of myeloid vs. NK/T-lymphoid progenitors.

Automated summary

The study identified a conserved differentially methylated region (DMR) in the CEBPA 3'-untranslated region (UTR) that is associated with AML cases displaying a myeloid/NK/T-cell phenotype and downregulated CEBPA expression. This DMR was found to enhance transcription from the CEBPA native promoter and was found to have IKZF1-binding sites responsible for the increased transcription of CEBPA. These findings suggest that the CEBPA 3'-UTR DMR is a novel regulatory element involved in myeloid/NK/T-cell lineage leukemogenesis.