The RUNX1–ETO fusion protein trans ‐activates c‐KIT expression by recruiting histone acetyltransferase P300 on its promoter

作者：Guofeng Chen, Anqi Liu, Yihan Xu, Li Gao, Mengmeng Jiang, Yan Li, Yan Li, Na Lv, Lei Zhou, Lili Wang, Li Yu, Yonghui Li, Yonghui Li · 发表于：FEBS Journal · 年份：2019 · DOI：10.1111/febs.14751 · 被引用次数：26 · 研究领域：Acute Myeloid Leukemia Research、Histone Deacetylase Inhibitors Research、Multiple Myeloma Research and Treatments

The oncoprotein RUNX1-ETO is the fusion product of t(8;21)(q22;q22) and constitutes one of the most common genetic alterations in acute myeloid leukemia (AML). Abnormal c-KIT overexpression is considered an independent negative prognostic factor for relapse and survival in t(8;21) AML patients. However, the molecular mechanism of high c-KIT expression in t(8;21) AML remains unknown. In this study, we detected RUNX1-ETO and c-KIT gene expression in AML-M2 patients and verified the overexpression of c-KIT in t(8;21) AML patients. We also found that c-KIT overexpression was a poor prognostic indicator in RUNX1-ETO positive AML patients, but not in RUNX1-ETO negative AML patients. We used the dual-luciferase and ChIP assays to demonstrate that the RUNX1-ETO protein epigenetically trans-activates c-KIT by binding to the c-KIT promoter and recruiting the histone acetyltransferase P300 to the c-KIT promoter, elucidating the mechanism of the abnormally increased c-KIT expression in t(8;21) AML patients. Moreover, pharmacological studies revealed that C646, a P300 inhibitor, could inhibit proliferation, induce apoptosis and arrest the cell cycle more effectively in RUNX1-ETO positive cells than in negative ones. The levels of c-KIT and RUNX1-ETO proteins were also decreased with C646 treatment in RUNX1-ETO positive cells. These findings suggested that P300 could be a therapeutic target and that C646 could be used as a potential treatment for RUNX1-ETO positive AML patients. Interestin...