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Published on: September 1, 2019
PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic
Dominik Beck1,2, Honghui Cao3, Feng Tian4
1Shanghai 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. Dominik.Beck@uts.edu.au.
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.
Insights
Glucocorticoid resistance in lymphoid cancers can be overcome by targeting the transcription factor PU.1. Inhibiting PU.1 enhances drug sensitivity, offering new therapeutic strategies for cancer treatment.
Area of Science:
- Epigenetics
- Cancer Biology
- Molecular Oncology
Background:
- Epigenetic alterations are crucial in cancer progression, particularly in lymphoid cancers treated with glucocorticoids.
- Therapeutic resistance to glucocorticoids, often linked to epigenetic changes, limits treatment efficacy.
- Understanding these epigenetic mechanisms is vital for developing effective cancer therapies.
Purpose of the Study:
- To investigate the role of epigenetic modifications and transcription factor PU.1 in glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia (ALL).
- To explore the interaction between PU.1 and the glucocorticoid receptor (GR) in regulating gene expression and therapeutic response.
- To evaluate the potential of targeting PU.1 as a strategy to overcome glucocorticoid resistance in lymphoid cancers.
Main Methods:
- Analysis of chromosomal organization patterns in glucocorticoid-sensitive and resistant ALL xenograft models following glucocorticoid treatment.
- Investigation of PU.1's role as a pioneer transcription factor interacting with the GR at glucocorticoid-response elements.
- Assessment of PU.1 inhibitor efficacy in enhancing glucocorticoid sensitivity and therapeutic response in preclinical models.
Main Results:
- Glucocorticoid treatment induced distinct chromosomal organization patterns in sensitive versus resistant ALL models.
- PU.1 primes glucocorticoid-response elements and its eviction facilitates GR binding and apoptosis-related gene expression.
- Inhibition of PU.1 significantly enhanced glucocorticoid sensitivity, leading to improved therapeutic outcomes.
Conclusions:
- A novel mechanism linking PU.1 transcription factor activity, GR interaction, and epigenetic regulation to glucocorticoid drug response in lymphoid cancers was uncovered.
- Targeting PU.1 represents a promising therapeutic strategy to overcome glucocorticoid resistance in acute lymphoblastic leukemia.
- This research provides a foundation for developing innovative treatments to improve patient outcomes in lymphoid malignancies.
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