Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methyl-cytosine 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.
基金：
University of Cincinnati College of Medicine Core Enhancement Funding; National Institutes of Health (NIH) [CA211614, CA178454, CA214965, CA182528, RM1 HG008935]; Gabrielle's Angel Foundation for Cancer Research; University of Chicago Committee on Cancer Biology (CCB) Fellowship Program; National Natural Science Foundation of Chongqing [cstc2015jcyjBX0100]; Foundation of Innovation Team for Basic and Clinical Research of Zhejiang Province [2011R50015]; NCI, NIH; NHGRI, NIH
语种：
外文
被引次数：
WOS：
PubmedID：
中科院(CAS)分区：
出版当年[2017]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
最新[2023]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
第一作者：
第一作者机构：[1]Univ Cincinnati, Dept Canc Biol, Cincinnati, OH 45219 USA;[2]Univ Chicago, Dept Med, Sect Hematol Oncol, 5841 S Maryland Ave, Chicago, IL 60637 USA;[3]City Hope Natl Med Ctr, Beckman Res Inst, Dept Syst Biol, Monrovia, CA 91016 USA;
通讯机构：[1]Univ Cincinnati, Dept Canc Biol, Cincinnati, OH 45219 USA;[2]Univ Chicago, Dept Med, Sect Hematol Oncol, 5841 S Maryland Ave, Chicago, IL 60637 USA;[3]City Hope Natl Med Ctr, Beckman Res Inst, Dept Syst Biol, Monrovia, CA 91016 USA;
推荐引用方式(GB/T 7714)：
Jiang Xi,Hu Chao,Ferchen Kyle,et al.Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia[J].NATURE COMMUNICATIONS.2017,8(1):-.doi:10.1038/s41467-017-02290-w.
APA：
Jiang, Xi,Hu, Chao,Ferchen, Kyle,Nie, Ji,Cui, Xiaolong...&Chen, Jianjun.(2017).Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia.NATURE COMMUNICATIONS,8,(1)
MLA：
Jiang, Xi,et al."Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia".NATURE COMMUNICATIONS 8..1(2017):-
综合性期刊