PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia
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.
Authors
- Samuel J. Taylor (ORCID: https://orcid.org/0000-0002-9468-8752)
- Timothy A. Couttas (ORCID: https://orcid.org/0000-0002-5896-2638)
- Miao Jiang (ORCID: https://orcid.org/0000-0002-7963-6022)
- Yizhou Huang (ORCID: https://orcid.org/0000-0002-7003-3110)
- Hansen J. Kosasih (ORCID: https://orcid.org/0000-0002-0428-6195)
- David Kealy (ORCID: https://orcid.org/0000-0001-9246-8134)
- Katherine S. Bridge (ORCID: https://orcid.org/0000-0003-1516-1459)
- Charles E. de Bock (ORCID: https://orcid.org/0000-0001-5182-8535)
- Richard B. Lock (ORCID: https://orcid.org/0000-0002-3436-9071)
- Andrew N. Holding (ORCID: https://orcid.org/0000-0002-8459-7048)
- Diego Chacon Fajardo (ORCID: https://orcid.org/0000-0003-3729-1385)
- Meng Wang (ORCID: https://orcid.org/0000-0003-0221-0653)
- Honghui Cao (ORCID: https://orcid.org/0009-0002-4279-4454)
- Duohui Jing (ORCID: https://orcid.org/0000-0002-1491-8002)
- Xiaolu Tai
- Feng Tian (ORCID: https://orcid.org/0000-0003-3552-4536)
- Adam Dowle (ORCID: https://orcid.org/0000-0002-6501-5444)
- Yashna Walia (ORCID: https://orcid.org/0009-0009-7886-7863)
- Chao Zhang (ORCID: https://orcid.org/0000-0001-6418-8370)
- Han Zhao (ORCID: https://orcid.org/0000-0001-6770-5396)
- Weiye Zhao (ORCID: https://orcid.org/0000-0003-1904-9560)
- Wenqian Xu (ORCID: https://orcid.org/0000-0002-4605-6769)
- Dominik Beck (ORCID: https://orcid.org/0000-0002-9908-4341)
- Jian‐Qing Mi (ORCID: https://orcid.org/0000-0002-0769-5437)
- Gaoxian Song
- Jin Wang
Institutions
- Hebei University of Engineering (CN)
- University of Technology Sydney (AU)
- The University of Sydney (AU)
- Albert Einstein College of Medicine (US)
- Shanghai Jiao Tong University (CN)
- Ruijin Hospital (CN)
- Cancer Institute of New South Wales (AU)
- UNSW Sydney (AU)
- Children's Cancer Institute Australia (AU)
- Shanghai First People's Hospital (CN)
- Shanghai Institute of Hematology (CN)
- University of York (GB)
- Neuroscience Research Australia (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-08
- DOI
- https://doi.org/10.1038/s41467-024-54096-2
- Citations
- 6
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 3.26
Funders
- Neuroscience Research Australia
- Yorkshire Forward
- Deutsche Forschungsgemeinschaft
- University of New South Wales
- University of Sydney
- University of Technology Sydney
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality
- Shanghai Jiao Tong University
- Hebei University
- Chinesisch-Deutsche Zentrum für Wissenschaftsförderung
- Hebei University of Engineering
- Kids Cancer Alliance
- Ruijin Hospital
- Translational Cancer Research Network
- Centre for Blood Research, University of British Columbia
- Medical Research Council
- Engineering and Physical Sciences Research Council
- Biotechnology and Biological Sciences Research Council
- National Health and Medical Research Council
- School of Medicine, Shanghai Jiao Tong University
- Faculty of Medicine and Health, University of Sydney