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Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia

Author

Listed:
  • Hanlin Wang

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    Fudan University
    University of Chinese Academy of Sciences)

  • Guanghao Luo

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xiaobei Hu

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Gaoya Xu

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    Nanjing University of Chinese Medicine)

  • Tao Wang

    (Naval Medical University)

  • Minmin Liu

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    Jiangnan University)

  • Xiaohui Qiu

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Jianan Li

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    Nanjing University of Chinese Medicine)

  • Jingfeng Fu

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Bo Feng

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    Shenyang Pharmaceutical University)

  • Yutong Tu

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Weijuan Kan

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Chang Wang

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Ran Xu

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    Nanjing University of Chinese Medicine)

  • Yubo Zhou

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Chinese Academy of Sciences
    Nanjing University of Chinese Medicine)

  • Jianmin Yang

    (Naval Medical University)

  • Jia Li

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    Fudan University
    University of Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

Abstract

The outcomes of FLT3-ITD acute myeloid leukaemia (AML) have been improved since the approval of FLT3 inhibitors (FLT3i). However, approximately 30-50% of patients exhibit primary resistance (PR) to FLT3i with poorly defined mechanisms, posing a pressing clinical unmet need. Here, we identify C/EBPα activation as a top PR feature by analyzing data from primary AML patient samples in Vizome. C/EBPα activation limit FLT3i efficacy, while its inactivation synergistically enhances FLT3i action in cellular and female animal models. We then perform an in silico screen and identify that guanfacine, an antihypertensive medication, mimics C/EBPα inactivation. Furthermore, guanfacine exerts a synergistic effect with FLT3i in vitro and in vivo. Finally, we ascertain the role of C/EBPα activation in PR in an independent cohort of FLT3-ITD patients. These findings highlight C/EBPα activation as a targetable PR mechanism and support clinical studies aimed at testing the combination of guanfacine with FLT3i in overcoming PR and enhancing the efficacy of FLT3i therapy.

Suggested Citation

  • Hanlin Wang & Guanghao Luo & Xiaobei Hu & Gaoya Xu & Tao Wang & Minmin Liu & Xiaohui Qiu & Jianan Li & Jingfeng Fu & Bo Feng & Yutong Tu & Weijuan Kan & Chang Wang & Ran Xu & Yubo Zhou & Jianmin Yang , 2023. "Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37381-4
    DOI: 10.1038/s41467-023-37381-4
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    References listed on IDEAS

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