Glucocorticoid receptor activation reorganizes Wnt/LEF1 regulatory circuitry associated with therapeutic…

Abstract

Glucocorticoids (GCs) are foundational to B-cell acute lymphoblastic leukemia (B-ALL) therapy, yet how glucocorticoid receptor (GR) activation interacts with lineage regulatory circuitry to shape therapeutic response remains incompletely understood. Using LEF1 to interrogate canonical Wnt regulatory circuitry, we show that GR activation reorganizes GR+LEF1 elements into recruitment, retention, and dissociation states. LEF1 dissociates from Wnt-responsive regulatory elements while being recruited to GRE-rich GR-associated elements that progressively acquire chromatin accessibility, H3K27ac, BRD4 and BRG1. RUNX1 and AP-1 show class-dependent redistribution across LEF1-defined states, extending organization beyond LEF1. GR+LEF1 reorganization is observed in patient-derived B-ALL. GR+LEF1 elements lose accessibility in GC-resistant B-ALL and during diagnosis-to-relapse evolution, with recruitment elements enriched for remodeling. Perturbation of resistance-associated GR+LEF1 elements at BIM and BMF alters GC-induced apoptotic signaling. Together, these findings identify Wnt/LEF1 circuitry as an interface through which therapeutic GR activation reorganizes the B-ALL regulatory landscape into states associated with glucocorticoid response and resistance.

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BibTeX

@misc{mobley2026glucocorticoid,
  title = {{Glucocorticoid receptor activation reorganizes Wnt/LEF1 regulatory circuitry associated with therapeutic response in B-cell acute lymphoblastic leukemia}},
  author = {R. J. Mobley and D. Oluwalana and G. Baniulyte and M. Zheng and B. Brown and F. Usrof and K. R. Bhattarai and K. R. Barnett and V. Valentine and M. Valentine and S. Staller and S. Yoshimura and K. R. Crews and D. T. Teachey and S. Burden and Y. Cheng and J. J. Yang and D. Savic},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.23.752002},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.23.752002v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Glucocorticoid receptor activation reorganizes Wnt/LEF1 regulatory circuitry associated with therapeutic response in B-cell acute lymphoblastic leukemia
AU  - R. J. Mobley
AU  - D. Oluwalana
AU  - G. Baniulyte
AU  - M. Zheng
AU  - B. Brown
AU  - F. Usrof
AU  - K. R. Bhattarai
AU  - K. R. Barnett
AU  - V. Valentine
AU  - M. Valentine
AU  - S. Staller
AU  - S. Yoshimura
AU  - K. R. Crews
AU  - D. T. Teachey
AU  - S. Burden
AU  - Y. Cheng
AU  - J. J. Yang
AU  - D. Savic
PY  - 2026
DA  - 2026/09/23
PB  - bioRxiv
DO  - 10.64898/2026.09.23.752002
UR  - https://www.biorxiv.org/content/10.64898/2026.09.23.752002v1
AB  - Glucocorticoids (GCs) are foundational to B-cell acute lymphoblastic leukemia (B-ALL) therapy, yet how glucocorticoid receptor (GR) activation interacts with lineage regulatory circuitry to shape therapeutic response remains incompletely understood. Using LEF1 to interrogate canonical Wnt regulatory circuitry, we show that GR activation reorganizes GR+LEF1 elements into recruitment, retention, and dissociation states. LEF1 dissociates from Wnt-responsive regulatory elements while being recruited to GRE-rich GR-associated elements that progressively acquire chromatin accessibility, H3K27ac, BRD4 and BRG1. RUNX1 and AP-1 show class-dependent redistribution across LEF1-defined states, extending organization beyond LEF1. GR+LEF1 reorganization is observed in patient-derived B-ALL. GR+LEF1 elements lose accessibility in GC-resistant B-ALL and during diagnosis-to-relapse evolution, with recruitment elements enriched for remodeling. Perturbation of resistance-associated GR+LEF1 elements at BIM and BMF alters GC-induced apoptotic signaling. Together, these findings identify Wnt/LEF1 circuitry as an interface through which therapeutic GR activation reorganizes the B-ALL regulatory landscape into states associated with glucocorticoid response and resistance.
ER  -

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