A regulatory element in the 3′‐untranslated region of CEBPA is associated with myeloid/NK/T‐cell leukemia
| Autor: | Yoshitaka Inoue, Kenji Tokunaga, Masao Matsuoka, Shinya Endo, Kouta Iwanaga, Yukiko Kimura, Yousuke Nagahata, Hiroshi Kawamoto, Eisaku Iwanaga, Kyoko Masuda |
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| Rok vydání: | 2020 |
| Předmět: |
Untranslated region
Myeloid Regulatory Sequences Nucleic Acid Biology Epigenesis Genetic Immunophenotyping 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases CEBPA medicine Humans Genetic Predisposition to Disease Myeloid Cells 3' Untranslated Regions Transcription factor Genetic Association Studies Acute leukemia Binding Sites Three prime untranslated region Myeloid leukemia Hematology General Medicine DNA Methylation Leukemia Biphenotypic Acute Phenotype medicine.anatomical_structure 030220 oncology & carcinogenesis DNA methylation CCAAT-Enhancer-Binding Proteins Cancer research Natural Killer T-Cells Biomarkers Protein Binding 030215 immunology |
| Zdroj: | European Journal of Haematology. 106:327-339 |
| ISSN: | 1600-0609 0902-4441 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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