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.

A minicircuitry of microRNA-9-1 and RUNX1-RUNX1T1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia

“…To determine the role of RUNX1‐RUNX1T1 in the regulation of miR‐9–1‐5p expression, RUNX1‐RUNX1T1 was knocked out in SKNO‐1 cells (SKNO‐1‐siAE) using a lentiviral vector, and HA‐tagged RUNX1‐RUNX1T1 cDNA was electroporated into U937 cells to produce the U937‐AE‐HA clone in a zinc‐inducible manner . Knockdown and overexpression of RUNX1‐RUNX1T1 by western blot in SKNO‐1‐siAE and U937‐AE‐HA were validated, respectively (Fig.…”

Histone Deacetylase Inhibitors Activate Tristetraprolin Expression through Induction of Early Growth Response Protein 1 (EGR1) in Colorectal Cancer Cells

“…The mechanism(s) by which HDAC inhibitors induce EGR1 expression and activity was not investigated in this study. Previous work has shown that HDAC inhibitors can reactivate EGR1 in various cell types, leading to decreased cell proliferation and increased cell apoptosis [ 25 , 46 , 47 , 48 ]. Other mechanisms controlling EGR1 include various signaling pathways such as the EGF (Epidermal Growth Factor)/ELK1 (Ets domain containing protein) pathway [ 24 ].…”

Egr1 mediates retinal vascular dysfunction in diabetes mellitus via promoting p53 transcription

“…5 Contrary to the activating growth function, overexpression of Egr1 inhibited the cell proliferation and promoted apoptosis, and knocking out Egr1 promoted cell proliferation. 6 All of these indicate that the effects of Egr1 are complicated and may depend on the type of disease.…”