Nature Communications (Nov 2024)
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,
- Duohui Jing
Affiliations
- Dominik Beck
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
- Honghui Cao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
- Feng Tian
- Hebei Key Laboratory of Medical Data Science, Institute of Biomedical Informatics, School of Medicine, Hebei University of Engineering
- Yizhou Huang
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Miao Jiang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
- Han Zhao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
- Xiaolu Tai
- Department of Orthopedics and Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
- Wenqian Xu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
- Hansen J. Kosasih
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- David J. Kealy
- Centre for Blood Research, University of York
- Weiye Zhao
- York Biomedical Research Institute, University of York
- Samuel J. Taylor
- Department of Cell Biology, Albert Einstein College of Medicine
- Timothy A. Couttas
- Neuroscience Research Australia
- Gaoxian Song
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
- Diego Chacon-Fajardo
- Centre for Health Technologies and the School of Biomedical Engineering, University of Technology
- Yashna Walia
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Meng Wang
- Department of Orthopedics and Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
- Adam A. Dowle
- Metabolomics & Proteomics Laboratory, Bioscience Technology Facility, Department of Biology, University of York
- Andrew N. Holding
- York Biomedical Research Institute, University of York
- Katherine S. Bridge
- Centre for Blood Research, University of York
- Chao Zhang
- Department of Orthopedics and Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
- Jin Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
- Jian-Qing Mi
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
- Richard B. Lock
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Charles E. de Bock
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Duohui Jing
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
- DOI
- https://doi.org/10.1038/s41467-024-54096-2
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
