Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia

Xi Jiang (), Chao Hu, Kyle Ferchen, Ji Nie, Xiaolong Cui, Chih-Hong Chen, Liting Cheng, Zhixiang Zuo, William Seibel, Chunjiang He, Yixuan Tang, Jennifer R. Skibbe, Mark Wunderlich, William C. Reinhold, Lei Dong, Chao Shen, Stephen Arnovitz, Bryan Ulrich, Jiuwei Lu, Hengyou Weng, Rui Su, Huilin Huang, Yungui Wang, Chenying Li, Xi Qin, James C. Mulloy, Yi Zheng, Jiajie Diao, Jie Jin, Chong Li, Paul P. Liu, Chuan He, Yuan Chen and Jianjun Chen ()
Additional contact information
Xi Jiang: University of Cincinnati
Chao Hu: University of Cincinnati
Kyle Ferchen: University of Cincinnati
Ji Nie: University of Chicago
Xiaolong Cui: University of Chicago
Chih-Hong Chen: Beckman Research Institute of City of Hope
Liting Cheng: Southwest University
Zhixiang Zuo: University of Cincinnati
William Seibel: Cincinnati Children’s Hospital Medical Center
Chunjiang He: Wuhan University
Yixuan Tang: Southwest University
Jennifer R. Skibbe: University of Cincinnati
Mark Wunderlich: Cincinnati Children’s Hospital Medical Center
William C. Reinhold: NIH
Lei Dong: University of Cincinnati
Chao Shen: University of Cincinnati
Stephen Arnovitz: University of Chicago
Bryan Ulrich: University of Chicago
Jiuwei Lu: University of Cincinnati
Hengyou Weng: University of Cincinnati
Rui Su: University of Cincinnati
Huilin Huang: University of Cincinnati
Yungui Wang: University of Cincinnati
Chenying Li: University of Cincinnati
Xi Qin: University of Cincinnati
James C. Mulloy: Cincinnati Children’s Hospital Medical Center
Yi Zheng: Cincinnati Children’s Hospital Medical Center
Jiajie Diao: University of Cincinnati
Jie Jin: Zhejiang University
Chong Li: Southwest University
Paul P. Liu: NIH
Chuan He: University of Chicago
Yuan Chen: Beckman Research Institute of City of Hope
Jianjun Chen: University of Cincinnati

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02290-w

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