Department of Molecular, Cell and Cancer Biology; Graduate School of Biomedical Sciences
Cancer Biology | Neoplasms
Synthetic glucocorticoids (GCs), such as dexamethasone and prednisone, remain key components of therapy for patients with lymphoid malignancies. For pediatric patients with acute lymphoblastic leukemia (ALL), response to GCs remains the most reliable prognostic indicator; failure to respond to GC correlates with poor event-free survival. To uncover GC resistance mechanisms, we performed a genome-wide, survival-based short hairpin RNA screen and identified the orphan nuclear receptor estrogen-related receptor-beta (ESRRB) as a critical transcription factor that cooperates with the GC receptor (GR) to mediate the GC gene expression signature in mouse and human ALL cells. Esrrb knockdown interfered with the expression of genes that were induced and repressed by GR and resulted in GC resistance in vitro and in vivo. Dexamethasone treatment stimulated ESRRB binding to estrogen-related receptor elements (ERREs) in canonical GC-regulated genes, and H3K27Ac Hi-chromatin immunoprecipitation revealed increased interactions between GR- and ERRE-containing regulatory regions in dexamethasone-treated human T-ALL cells. Furthermore, ESRRB agonists enhanced GC target gene expression and synergized with dexamethasone to induce leukemic cell death, indicating that ESRRB agonists may overcome GC resistance in ALL, and potentially, in other lymphoid malignancies.
Lymphoid Neoplasia, acute lymphocytic leukemia, adult t-cell lymphoma/leukemia, dexamethasone, gene expression, genes, leukemic cells, mice, t-cell leukemia, acute, glucocorticoids, agonists
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DOI of Published Version
Gallagher KM, Roderick JE, Tan SH, Tan TK, Murphy L, Yu J, Li R, O'Connor KW, Zhu J, Green MR, Sanda T, Kelliher MA. ESRRB regulates glucocorticoid gene expression in mice and patients with acute lymphoblastic leukemia. Blood Adv. 2020 Jul 14;4(13):3154-3168. doi: 10.1182/bloodadvances.2020001555. PMID: 32658986; PMCID: PMC7362368. Link to article on publisher's site
Gallagher KM, Roderick JE, Tan SH, Tan TK, Murphy L, Yu J, Li R, O'Connor K, Zhu LJ, Green MR, Sanda T, Kelliher MA. (2020). ESRRB regulates glucocorticoid gene expression in mice and patients with acute lymphoblastic leukemia. Open Access Publications by UMMS Authors. https://doi.org/10.1182/bloodadvances.2020001555. Retrieved from https://escholarship.umassmed.edu/oapubs/4285