1区 · 综合性期刊
ArticleOA
作者: Seibel, William ; Skibbe, Jennifer R ; Wang, Yungui ; Arnovitz, Stephen ; Nie, Ji ; Reinhold, William C ; Cheng, Liting ; Qin, Xi ; Diao, Jiajie ; Zuo, Zhixiang ; Wunderlich, Mark ; Jin, Jie ; Chen, Chih-Hong ; Zheng, Yi ; Li, Chong ; Liu, Paul P ; Cui, Xiaolong ; Jiang, Xi ; Chen, Jianjun ; Dong, Lei ; Mulloy, James C ; He, Chuan ; Hu, Chao ; Huang, Huilin ; Chen, Yuan ; Su, Rui ; Lu, Jiuwei ; Shen, Chao ; Weng, Hengyou ; Ferchen, Kyle ; Tang, Yixuan ; Li, Chenying ; Ulrich, Bryan ; He, Chunjiang
Abstract:Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Through a series of data analysis and drug screening, we identified two compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high expression of TET1 (i.e., TET1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML. NSC-311068 and especially NSC-370284 significantly repressed TET1-high AML progression in vivo. UC-514321, a structural analog of NSC-370284, exhibited a more potent therapeutic effect and prolonged the median survival of TET1-high AML mice over three fold. NSC-370284 and UC-514321 both directly target STAT3/5, transcriptional activators of TET1, and thus repress TET1 expression. They also exhibit strong synergistic effects with standard chemotherapy. Our results highlight the therapeutic potential of targeting the STAT/TET1 axis by selective inhibitors in AML treatment.
