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

Yukiko Kimura, Eisaku Iwanaga, Kouta Iwanaga, Shinya Endo, Yoshitaka Inoue, Kenji Tokunaga, Yousuke Nagahata, Kyoko Masuda, Hiroshi Kawamoto, Masao Matsuoka

研究成果: Article査読

抄録

Objectives: CCAAT/enhancer-binding protein α (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.

本文言語English
ページ(範囲)327-339
ページ数13
ジャーナルEuropean Journal of Haematology
106
3
DOI
出版ステータスPublished - 03-2021
外部発表はい

All Science Journal Classification (ASJC) codes

  • 血液学

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