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

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, Gaoxian Song, Diego Chacon-Fajardo, Yashna Walia, Meng Wang, Adam A. Dowle, Andrew N. Holding, Katherine S. Bridge, Chao Zhang, Jin Wang, Jian-Qing Mi, Richard B. Lock (), Charles E. de Bock () and Duohui Jing ()
Additional contact information
Dominik Beck: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
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
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

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54096-2

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