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PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia

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Listed:
  • Dominik Beck

    (Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
    University of Technology)

  • Honghui Cao

    (Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Feng Tian

    (Hebei University of Engineering)

  • Yizhou Huang

    (UNSW Sydney)

  • Miao Jiang

    (Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Han Zhao

    (Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Xiaolu Tai

    (Shanghai Jiao Tong University School of Medicine)

  • Wenqian Xu

    (Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Hansen J. Kosasih

    (UNSW Sydney)

  • David J. Kealy

    (University of York)

  • Weiye Zhao

    (University of York)

  • Samuel J. Taylor

    (Albert Einstein College of Medicine)

  • Timothy A. Couttas

    (Neuroscience Research Australia
    The University of Sydney)

  • Gaoxian Song

    (Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Diego Chacon-Fajardo

    (University of Technology)

  • Yashna Walia

    (UNSW Sydney)

  • Meng Wang

    (Shanghai Jiao Tong University School of Medicine)

  • Adam A. Dowle

    (University of York)

  • Andrew N. Holding

    (University of York)

  • Katherine S. Bridge

    (University of York)

  • Chao Zhang

    (Shanghai Jiao Tong University School of Medicine)

  • Jin Wang

    (Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Jian-Qing Mi

    (Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Richard B. Lock

    (UNSW Sydney)

  • Charles E. de Bock

    (UNSW Sydney)

  • Duohui Jing

    (Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

Abstract

The epigenetic landscape plays a critical role in cancer progression, yet its therapeutic potential remains underexplored. Glucocorticoids are essential components of treatments for lymphoid cancers, but resistance, driven in part by epigenetic changes at glucocorticoid-response elements, poses a major challenge to effective therapies. Here we show that glucocorticoid treatment induces distinct patterns of chromosomal organization in glucocorticoid-sensitive and resistant acute lymphoblastic leukemia xenograft models. These glucocorticoid-response elements are primed by the pioneer transcription factor PU.1, which interacts with the glucocorticoid receptor. Eviction of PU.1 promotes receptor binding, increasing the expression of genes involved in apoptosis and facilitating a stronger therapeutic response. Treatment with a PU.1 inhibitor enhances glucocorticoid sensitivity, demonstrating the clinical potential of targeting this pathway. This study uncovers a mechanism involving PU.1 and the glucocorticoid receptor, linking transcription factor activity with drug response, and suggesting potential therapeutic strategies for overcoming resistance.

Suggested Citation

  • Dominik Beck & Honghui Cao & Feng Tian & Yizhou Huang & Miao Jiang & Han Zhao & Xiaolu Tai & Wenqian Xu & Hansen J. Kosasih & David J. Kealy & Weiye Zhao & Samuel J. Taylor & Timothy A. Couttas & Gaox, 2024. "PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54096-2
    DOI: 10.1038/s41467-024-54096-2
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