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A regulatory element in the 3′‐untranslated region of CEBPA is associated with myeloid/NK/T‐cell leukemia
Author(s) -
Kimura Yukiko,
Iwanaga Eisaku,
Iwanaga Kouta,
Endo Shinya,
Inoue Yoshitaka,
Tokunaga Kenji,
Nagahata Yousuke,
Masuda Kyoko,
Kawamoto Hiroshi,
Matsuoka Masao
Publication year - 2021
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.13551
Subject(s) - cebpa , myeloid leukemia , biology , untranslated region , myeloid , transcription factor , three prime untranslated region , cancer research , gene silencing , methylation , promoter , microbiology and biotechnology , genetics , gene , gene expression , messenger rna
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.