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CDK9 recruits HUWE1 to degrade RARα and offers therapeutic opportunities for cutaneous T-cell lymphoma

Author

Listed:
  • Chen-Hui Luo

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University)

  • Li-Hong Hu

    (Shanghai Jiao Tong University)

  • Jie-Yang Liu

    (Shanghai Jiao Tong University)

  • Li Xia

    (Shanghai Jiao Tong University School of Medicine)

  • Li Zhou

    (Shanghai Jiao Tong University School of Medicine)

  • Ren-Hong Sun

    (Gluetacs Therapeutics (Shanghai) Co., Ltd.)

  • Chen-Cen Lin

    (ShanghaiTech University)

  • Xing Qiu

    (ShanghaiTech University)

  • Biao Jiang

    (ShanghaiTech University)

  • Meng-Ying Yang

    (Shanghai Jiao Tong University)

  • Xue-Hong Zhang

    (Dalian Medical University)

  • Xiao-Bao Yang

    (Gluetacs Therapeutics (Shanghai) Co., Ltd.)

  • Guo-Qiang Chen

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine
    Hainan Medical University)

  • Ying Lu

    (Shanghai Jiao Tong University)

Abstract

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous non-Hodgkin lymphoma originating in the skin and invading the systemic hematopoietic system. Current treatments, including chemotherapy and monoclonal antibodies yielded limited responses with high incidence of side effects, highlighting the need for targeted therapy. Screening with small inhibitors library, herein we identify cyclin dependent kinase 9 (CDK9) as a driver of CTCL growth. Single-cell RNA-seq analysis reveals a CDK9high malignant T cell cluster with a unique actively proliferating feature. Inhibition, depletion or proteolysis targeting chimera (PROTAC)-mediated degradation of CDK9 significantly reduces CTCL cell growth in vitro and in murine models. CDK9 also promotes degradation of retinoic acid receptor α (RARα) via recruiting the E3 ligase HUWE1. Co-administration of CDK9-PROTAC (GT-02897) with all-trans retinoic acid (ATRA) leads to synergistic attenuation of tumor growth in vitro and in xenograft models, providing a potential translational treatment for complete eradication of CTCL.

Suggested Citation

  • Chen-Hui Luo & Li-Hong Hu & Jie-Yang Liu & Li Xia & Li Zhou & Ren-Hong Sun & Chen-Cen Lin & Xing Qiu & Biao Jiang & Meng-Ying Yang & Xue-Hong Zhang & Xiao-Bao Yang & Guo-Qiang Chen & Ying Lu, 2024. "CDK9 recruits HUWE1 to degrade RARα and offers therapeutic opportunities for cutaneous T-cell lymphoma," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54354-3
    DOI: 10.1038/s41467-024-54354-3
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