Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia PMID: 29235481

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2017 Dec 13;8(1):2099. doi: 10.1038/s41467-017-02290-w.

Xi Jiang ¹ ² ³ , Chao Hu ⁴ ⁵ ⁶ , Kyle Ferchen ⁴ , Ji Nie ⁷ , Xiaolong Cui ⁷ , Chih-Hong Chen ⁸ , Liting Cheng ⁹ , Zhixiang Zuo ⁴ ¹⁰ , William Seibel ¹¹ , Chunjiang He ¹² , Yixuan Tang ⁹ , Jennifer R Skibbe ⁴ , Mark Wunderlich ¹³ , William C Reinhold ¹⁴ , Lei Dong ⁴ ¹⁵ , Chao Shen ⁴ ¹⁵ , Stephen Arnovitz ⁵ , Bryan Ulrich ⁵ , Jiuwei Lu ⁴ , Hengyou Weng ⁴ ⁵ ¹⁵ , Rui Su ⁴ ¹⁵ , Huilin Huang ⁴ ¹⁵ , Yungui Wang ⁴ ⁵ ⁶ , Chenying Li ⁴ ¹⁵ ⁶ , Xi Qin ⁴ ¹⁵ , James C Mulloy ¹³ , Yi Zheng ¹³ , Jiajie Diao ⁴ , Jie Jin ⁶ , Chong Li ⁹ , Paul P Liu ¹⁶ , Chuan He ⁷ , Yuan Chen ⁸ , Jianjun Chen ¹⁷ ¹⁸ ¹⁹

Affiliations

1. Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, 45219, USA. [email protected].
2. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, 60637, USA. [email protected].
3. Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, 91016, USA. [email protected].
4. Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, 45219, USA.
5. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, 60637, USA.
6. Department of Hematology, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
7. Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL, 60637, USA.
8. Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
9. Key Laboratory of Luminescence and Real-time Analytical Chemistry (Ministry of Education), College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.
10. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
11. Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
12. School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
13. Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
14. Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, 20892, USA.
15. Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, 91016, USA.
16. Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA.
17. Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, 45219, USA. [email protected].
18. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, 60637, USA. [email protected].
19. Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, 91016, USA. [email protected].

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.