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AML 1– ETO triggers epigenetic activation of early growth response gene l, inducing apoptosis in t(8;21) acute myeloid leukemia
Author(s) -
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
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12673
Subject(s) - myeloid leukemia , trichostatin a , cancer research , histone acetyltransferase , histone deacetylase inhibitor , cell growth , epigenetics , methyltransferase , biology , histone deacetylase , histone , dna methylation , dna methyltransferase , chromosomal translocation , microbiology and biotechnology , methylation , gene expression , gene , genetics
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 ( AML 1 ) – myeloid transforming gene 8 ( ETO )‐positive AML , which has a relatively favorable prognosis. However, the molecular mechanism related to a favorable prognosis in AML 1– 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 ( EGR 1 ) by binding at AML 1‐binding sites on the EGR 1 promoter and, subsequently, recruiting acetyltransferase P300, which is known to acetylate histones. However, AML 1– ETO could not recruit DNA methyltransferases and histone deacetylases; therefore, EGR 1 expression was affected by histone acetylation but not by DNA methylation. Both transcription and translation of EGR 1 were higher in AML 1– ETO ‐positive AML cell lines than in AML 1– ETO ‐negative AML cell lines, owing to acetylation. Furthermore, when AML 1– ETO ‐positive AML cell lines were treated with C646 (P300 inhibitor) and trichostatin A (histone deacetylase inhibitor), EGR 1 expression was significantly decreased and increased, respectively. In addition, treatment with 5‐azacytidine (methyltransferase inhibitor) did not cause any significant change in EGR 1 expression. Overexpression of EGR 1 inhibited cell proliferation and promoted apoptosis, and EGR 1 knockout promoted cell proliferation. Thus, EGR 1 could be a novel prognostic factor for a favorable outcome in AML 1– ETO ‐positive AML . The results of our study may explain the molecular mechanisms underlying the favorable prognosis in AML 1– ETO ‐positive AML .