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

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 1

JAK/STAT inhibition overcomes DEX resistance in a subset of primary T-ALL samples and in the T-ALL cell line CCRF-CEM.

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JAK/STAT inhibition overcomes DEX resistance in a subset of primary T-AL...
(A) Viability relative to vehicle control of cells from 73 primary diagnostic T-ALL samples exposed to 2.5 μM DEX for 48 hours in the presence of 25 ng/mL IL-7. The red line indicates the 50% viability cutoff used to define DEX resistance. (B) Viability of cells from the 46 DEX-resistant primary diagnostic T-ALL samples in A exposed to 2.5 μM DEX and/or 0.5 μM RUX for 48 hours in the presence of 25 ng/mL IL-7, relative to vehicle control cells. ****P < 0.0001, by 1-way ANOVA with Tukey’s method for multiple comparisons adjustment. (C) Viability of CCRF-CEM cells exposed for 72 hours to DEX in the absence or presence of increasing concentrations of IL-7. The experiment was performed in technical triplicate. (D) Viability of CCRF-CEM cells exposed to DEX in the presence of 25 ng/mL IL-7 in the absence or presence of increasing concentrations of RUX. The experiment was performed in technical triplicate. The “No IL-7” (black line) and the 25 ng/mL IL-7 (red line) conditions were replotted from Figure 1C. (E) Heatmap of Bliss independence scores calculated as the average of technical triplicates for the combination of DEX and RUX in CCRF-CEM cells cultured in the presence of 25 ng/mL IL-7 for 72 hours, in which positive values, indicated in red, are indicative of a synergistic interaction. All CCRF-CEM cell data are representative of 3 independent experiments.