title: AML1-ETO triggers epigenetic activation of early growth response gene l, inducing apoptosis in t(8;21) acute myeloid leukemia.
abstract: 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 (AML1)-myeloid transforming gene 8 (ETO)-positive AML, which has a relatively favorable prognosis. However, the molecular mechanism related to a favorable prognosis in AML1-ETO-positive AML is still not fully understood. Our results show that the AML1-ETO fusion protein triggered activation of early growth response gene l (EGR1) by binding at AML1-binding sites on the EGR1 promoter and, subsequently, recruiting acetyltransferase P300, which is known to acetylate histones. However, AML1-ETO could not recruit DNA methyltransferases and histone deacetylases; therefore, EGR1 expression was affected by histone acetylation but not by DNA methylation. Both transcription and translation of EGR1 were higher in AML1-ETO-positive AML cell lines than in AML1-ETO-negative AML cell lines, owing to acetylation. Furthermore, when AML1-ETO-positive AML cell lines were treated with C646 (P300 inhibitor) and trichostatin A (histone deacetylase inhibitor), EGR1 expression was significantly decreased and increased, respectively. In addition, treatment with 5-azacytidine (methyltransferase inhibitor) did not cause any significant change in EGR1 expression. Overexpression of EGR1 inhibited cell proliferation and promoted apoptosis, and EGR1 knockout promoted cell proliferation. Thus, EGR1 could be a novel prognostic factor for a favorable outcome in AML1-ETO-positive AML. The results of our study may explain the molecular mechanisms underlying the favorable prognosis in AML1-ETO-positive AML.
authors: Department of Hematology, Chinese PLA General Hospital, Beijing, China; Nankai University School of Medicine, Tianjin, China.
authors: Lin
authors: L
authors: Fu
authors: Wenrong
authors: W
authors: Huang
authors: Yu
authors: Y
authors: Jing
authors: Mengmeng
authors: M
authors: Jiang
authors: Yu
authors: Y
authors: Zhao
authors: Jinglong
authors: J
authors: Shi
authors: Sai
authors: S
authors: Huang
authors: Xue
authors: X
authors: Xue
authors: Qingyi
authors: Q
authors: Zhang
authors: Juying
authors: J
authors: Tang
authors: Liping
authors: L
authors: Dou
authors: Lili
authors: L
authors: Wang
authors: Clara
authors: C
authors: Nervi
authors: Yonghui
authors: Y
authors: Li
authors: Li
authors: L
authors: Yu
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000235:genetics* / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase
keywords: AML1-ETO; P300; acetylation; acute myeloid leukemia; early growth response gene l