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

Author

Listed:
  • Xi Jiang

    (University of Cincinnati
    University of Chicago
    Beckman Research Institute of City of Hope)

  • Chao Hu

    (University of Cincinnati
    University of Chicago
    Zhejiang University)

  • 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
    Collaborative Innovation Center for Cancer Medicine)

  • 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
    Beckman Research Institute of City of Hope)

  • Chao Shen

    (University of Cincinnati
    Beckman Research Institute of City of Hope)

  • Stephen Arnovitz

    (University of Chicago)

  • Bryan Ulrich

    (University of Chicago)

  • Jiuwei Lu

    (University of Cincinnati)

  • Hengyou Weng

    (University of Cincinnati
    University of Chicago
    Beckman Research Institute of City of Hope)

  • Rui Su

    (University of Cincinnati
    Beckman Research Institute of City of Hope)

  • Huilin Huang

    (University of Cincinnati
    Beckman Research Institute of City of Hope)

  • Yungui Wang

    (University of Cincinnati
    University of Chicago
    Zhejiang University)

  • Chenying Li

    (University of Cincinnati
    Beckman Research Institute of City of Hope
    Zhejiang University)

  • Xi Qin

    (University of Cincinnati
    Beckman Research Institute of City of Hope)

  • 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
    University of Chicago
    Beckman Research Institute of City of Hope)

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.

Suggested Citation

  • 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 , 2017. "Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02290-w
    DOI: 10.1038/s41467-017-02290-w
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