AML1–ETO triggers epigenetic activation of early growth response gene l, inducing apoptosis in t(8;21) acute myeloid leukemia. (10th January 2014)

• Record Type: Journal Article
• Authors: Fu, Lin; Huang, Wenrong; Jing, Yu; Jiang, Mengmeng; Zhao, Yu; Shi, Jinglong; Huang, Sai; Xue, Xue; Zhang, Qingyi; Tang, Juying; Dou, Liping; Wang, Lili; Nervi, Clara; Li, Yonghui; Yu, Li
• Is Part Of: FEBS journal. Volume 281:Number 4(2014)
• Page Start: 1123
• Page End: 1131
• Publication Date: 2014-01-10
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.12673
• Languages: English
• ISSNs: 1742-464X

Abstract

<abstract abstract-type="main" id="febs12673-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>The t(8;21)(q22;q22) translocation is the most common chromosomal translocation in acute myeloid leukemia (AML), and it gives rise to acute myeloid gene 1 (<italic>AML1</italic>)<italic>–</italic>myeloid transforming gene 8 (<italic>ETO</italic>)‐positive AML, which has a relatively favorable prognosis. However, the molecular mechanism related to a favorable prognosis in <italic>AML1–ETO</italic>‐positive AML is still not fully understood. Our results show that the <italic>AML1–ETO</italic> fusion protein triggered activation of early growth response gene l (<italic>EGR1</italic>) by binding at AML1‐binding sites on the <italic>EGR1</italic> promoter and, subsequently, recruiting acetyltransferase P300, which is known to acetylate histones. However, AML1–ETO could not recruit DNA methyltransferases and histone deacetylases; therefore, <italic>EGR1</italic> expression was affected by histone acetylation but not by DNA methylation. Both transcription and translation of <italic>EGR1</italic> were higher in <italic>AML1–ETO</italic>‐positive AML cell lines than in <italic>AML1–ETO</italic>‐negative AML cell lines, owing to acetylation. Furthermore, when <italic>AML1–ETO</italic>‐positive AML cell lines were treated with C646 (P300 inhibitor) and trichostatin A (histone deacetylase inhibitor), <italic>EGR1</italic> expression was significantly decreased and increased, respectively. In addition, treatment with 5‐azacytidine (methyltransferase inhibitor) did not cause any significant change in <italic>EGR1</italic> expression. Overexpression of <italic>EGR1</italic> inhibited cell proliferation and promoted apoptosis, and <italic>EGR1</italic> knockout promoted cell proliferation. Thus, <italic>EGR1</italic> could be a novel prognostic factor for a favorable outcome in <italic>AML1–ETO</italic>‐positive AML. The results of our study may explain the molecular mechanisms underlying the favorable prognosis in <italic>AML1–ETO</italic>‐positive AML.</p> </abstract>