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

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

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

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