Department of Hematology, Rheumatology and Infectious Diseases, Kumamoto University, Kumamoto, Japan.
Laboratory of Immunology, Institute for Frontier Life and Medical Science, Kyoto University, Kyoto, Japan.
Eur J Haematol. 2021 Mar;106(3):327-339. doi: 10.1111/ejh.13551. Epub 2020 Nov 29.
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.
Using databases, we identified a conserved DMR in the CEBPA 3'-untranslated region (UTR).
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.
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.
CCAAT/增强子结合蛋白α（CEBPA）是骨髓细胞分化所必需的转录因子。不仅 CEBPA 基因突变，而且启动子甲基化导致 CEBPA 沉默，也有助于急性髓细胞白血病（AML）的发病机制。我们寻找另一个与 CEBPA 沉默和疾病表型相关的差异甲基化区域（DMR）。
使用数据库，我们在 CEBPA 3'非翻译区（UTR）中鉴定了一个保守的 DMR。
对 231 例 AML 病例的甲基化特异性 PCR 分析表明，3'UTR 的高甲基化与具有髓系/NK/T 细胞表型和下调 CEBPA 的 AML 相关。这些病例大多数为具有 CD7/CD56 阳性的不成熟表型。这些病例与其他病例相比，血红蛋白水平明显较低。此外，我们发现 CEBPA 3'UTR DMR 可以增强 CEBPA 天然启动子的转录。体外实验鉴定了 3'UTR 中的 IKZF1 结合位点，负责 CEBPA 的这种转录增强。
这些结果表明，CEBPA 3'UTR DMR 是与髓系/NK/T 细胞谱系白血病发生相关的 CEBPA 的新型调节元件。IKZF1 对 CEBPA 的转录调控可能为理解髓系与 NK/T 淋巴细胞祖细胞的命运决定提供线索。
