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Glucocorticoids paradoxically facilitate steroid resistance in T cell acute lymphoblastic leukemias and thymocytes
Lauren K. Meyer, … , David T. Teachey, Michelle L. Hermiston
Lauren K. Meyer, … , David T. Teachey, Michelle L. Hermiston
Published November 5, 2019
Citation Information: J Clin Invest. 2020;130(2):863-876. https://doi.org/10.1172/JCI130189.
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Research Article Oncology

Glucocorticoids paradoxically facilitate steroid resistance in T cell acute lymphoblastic leukemias and thymocytes

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Abstract

Glucocorticoids (GCs) are a central component of therapy for patients with T cell acute lymphoblastic leukemia (T-ALL), and although resistance to GCs is a strong negative prognostic indicator in T-ALL, the mechanisms of GC resistance remain poorly understood. Using diagnostic samples from patients enrolled in the frontline Children’s Oncology Group (COG) T-ALL clinical trial AALL1231, we demonstrated that one-third of primary T-ALLs were resistant to GCs when cells were cultured in the presence of IL-7, a cytokine that is critical for normal T cell function and that plays a well-established role in leukemogenesis. We demonstrated that in these T-ALLs and in distinct populations of normal developing thymocytes, GCs paradoxically induced their own resistance by promoting upregulation of IL-7 receptor (IL-7R) expression. In the presence of IL-7, this augmented downstream signal transduction, resulting in increased STAT5 transcriptional output and upregulation of the prosurvival protein BCL-2. Taken together, we showed that IL-7 mediates an intrinsic and physiologic mechanism of GC resistance in normal thymocyte development that is retained during leukemogenesis in a subset of T-ALLs and is reversible with targeted inhibition of the IL-7R/JAK/STAT5/BCL-2 axis.

Authors

Lauren K. Meyer, Benjamin J. Huang, Cristina Delgado-Martin, Ritu P. Roy, Aaron Hechmer, Anica M. Wandler, Tiffaney L. Vincent, Paolo Fortina, Adam B. Olshen, Brent L. Wood, Terzah M. Horton, Kevin M. Shannon, David T. Teachey, Michelle L. Hermiston

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Figure 5

IL-7 induces DEX resistance in subpopulations of normal developing thymocytes.

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IL-7 induces DEX resistance in subpopulations of normal developing thymo...
(A) Percentage of thymocyte subpopulations in thymi isolated from mice treated with vehicle control (n = 3) or DEX (n = 3) at 2 mg/kg/day for 3 days. (B) Percentage of priming of thymocytes in the basal state following BH3 profiling with 1 μM synthetic BIM peptide in technical triplicate for 90 minutes. (C) Histograms of the basal expression of IL-7Rα in the major murine thymocyte subpopulations. (D) Histograms of p-STAT5 in the major murine thymocyte subpopulations in the basal state (white histograms) and following a 15-minute stimulation with 100 ng/mL IL-7 (colored histograms). (E) Viability of murine thymocyte subpopulations following ex vivo treatment for 24 hours with DEX in the absence or presence of increasing concentrations of IL-7. (F) MFI of IL-7Rα in murine thymocytes treated ex vivo in the presence of 100 pg/mL IL-7 with or without 1 μM DEX in technical triplicate for 24 hours. DP cells could not be analyzed (NA) because of a lack of viable cells remaining after DEX exposure. (G) MFI of BCL-2 in murine thymocytes treated ex vivo in the presence of 100 pg/mL IL-7 with or without 1 μM DEX in technical triplicate for 24 hours. DP cells could not be analyzed (NA) because of a lack of viable cells remaining after DEX exposure. (H) MFI of BCL-2 in thymocytes isolated from mice treated with vehicle control (n = 3) or DEX (n = 3) at a dose of 2 mg/kg/day for 3 days. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-sample t test (A, F, G, and H) or 1-way ANOVA with Tukey’s method for multiple comparisons adjustment (B). All data are representative of 3 independent experiments.
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