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

doi:10.1038/s41467-024-54096-2

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

Nat Commun. 2024 Nov 8;15(1):9697. doi: 10.1038/s41467-024-54096-2.

Authors

Dominik Beck^#^{1

2}, Honghui Cao^#³, Feng Tian^#⁴, Yizhou Huang^#⁵, Miao Jiang³, Han Zhao³, Xiaolu Tai⁶, Wenqian Xu³, Hansen J Kosasih⁵, David J Kealy⁷, Weiye Zhao⁸, Samuel J Taylor⁹, Timothy A Couttas^{10

11}, Gaoxian Song³, Diego Chacon-Fajardo¹², Yashna Walia⁵, Meng Wang⁶, Adam A Dowle¹³, Andrew N Holding⁸, Katherine S Bridge⁷, Chao Zhang⁶, Jin Wang³, Jian-Qing Mi³, Richard B Lock¹⁴, Charles E de Bock¹⁵, Duohui Jing¹⁶

Affiliations

¹ 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, Shanghai, China. [email protected].
² Centre for Health Technologies and the School of Biomedical Engineering, University of Technology, Sydney, NSW, Australia. [email protected].
³ 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, Shanghai, China.
⁴ Hebei Key Laboratory of Medical Data Science, Institute of Biomedical Informatics, School of Medicine, Hebei University of Engineering, Handan, Hebei Province, China.
⁵ Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia.
⁶ Department of Orthopedics and Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁷ Centre for Blood Research, University of York, England, UK.
⁸ York Biomedical Research Institute, University of York, England, UK.
⁹ Department of Cell Biology, Albert Einstein College of Medicine, Randwick, NY, USA.
¹⁰ Neuroscience Research Australia, Randwick, NSW, Australia.
¹¹ Brain and Mind Centre, Translational Research Collective, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
¹² Centre for Health Technologies and the School of Biomedical Engineering, University of Technology, Sydney, NSW, Australia.
¹³ Metabolomics & Proteomics Laboratory, Bioscience Technology Facility, Department of Biology, University of York, England, UK.
¹⁴ Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia. [email protected].
¹⁵ Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia. [email protected].
¹⁶ 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, Shanghai, China. [email protected].

^# Contributed equally.

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.

MeSH terms

Animals
Apoptosis / drug effects
Cell Line, Tumor
Chromatin* / metabolism
Drug Resistance, Neoplasm / genetics
Epigenesis, Genetic / drug effects
Female
Gene Expression Regulation, Leukemic / drug effects
Glucocorticoids* / pharmacology
Humans
Lymphocytes / drug effects
Lymphocytes / metabolism
Mice
Precursor Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma* / genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma* / metabolism
Proto-Oncogene Proteins* / genetics
Proto-Oncogene Proteins* / metabolism
Receptors, Glucocorticoid* / genetics
Receptors, Glucocorticoid* / metabolism
Response Elements
Trans-Activators* / genetics
Trans-Activators* / metabolism
Xenograft Model Antitumor Assays

Substances

proto-oncogene protein Spi-1
Trans-Activators
Chromatin
Glucocorticoids
Receptors, Glucocorticoid
Proto-Oncogene Proteins

Abstract

MeSH terms

Substances

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