Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia. - Literature - Data resources

29235481

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

Nat Commun, 2017/12/13;8(1):2099.

Jiang X^{[1, 2, 3]}, Hu C^{[4, 5, 6]}, Ferchen K^[4], Nie J^[7], Cui X^[7], Chen CH^[8], Cheng L^[9], Zuo Z^{[4, 10]}, Seibel W^[11], He C^[12], Tang Y^[9], Skibbe JR^[4], Wunderlich M^[13], Reinhold WC^[14], Dong L^{[4, 15]}, Shen C^{[4, 15]}, Arnovitz S^[5], Ulrich B^[5], Lu J^[4], Weng H^{[4, 5, 15]}, Su R^{[4, 15]}, Huang H^{[4, 15]}, Wang Y^{[4, 5, 6]}, Li C^{[4, 15, 6]}, Qin X^{[4, 15]}, Mulloy JC^[13], Zheng Y^[13], Diao J^[4], Jin J^[6], Li C^[9], Liu PP^[16], He C^[7], Chen Y^[8], Chen J^{[17, 18, 19]}

Affiliations

Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, 45219, USA. xjiang@coh.org.
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, 60637, USA. xjiang@coh.org.
Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, 91016, USA. xjiang@coh.org.
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, 45219, USA.
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, 60637, USA.
Department of Hematology, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL, 60637, USA.
Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
Key Laboratory of Luminescence and Real-time Analytical Chemistry (Ministry of Education), College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, 20892, USA.
Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, 91016, USA.
Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA.
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, 45219, USA. jianchen@coh.org.
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, 60637, USA. jianchen@coh.org.
Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, 91016, USA. jianchen@coh.org.

PMID: 29235481DOI: 10.1038/s41467-017-02290-w

Impact factor: 17.694

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.

MeSH terms

Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Daunorubicin; Enzyme Inhibitors; Gene Expression Regulation, Leukemic; Humans; Kaplan-Meier Estimate; Leukemia, Experimental; Leukemia, Myeloid, Acute; Mice, Inbred C57BL; Mixed Function Oxygenases; Proto-Oncogene Proteins; RNA Interference; STAT3 Transcription Factor; STAT5 Transcription Factor; THP-1 Cells

More resources

Full text: Europe PubMed Central; PubMed Central

EndNote: Download