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 2

DEX exposure augments IL-7R expression and downstream JAK/STAT signaling.

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DEX exposure augments IL-7R expression and downstream JAK/STAT signaling...
(A) Viability of scrambled control (S1 and S2) and IL-7Rα KO (I1 and I2) CCRF-CEM cell clones exposed for 72 hours to DEX in the absence (solid lines) or presence (dotted lines) of 25 ng/mL IL-7. The experiment was performed in technical triplicate. (B) Fold change relative to the 16-hour time point of the ΔCt of IL7RA transcript levels relative to GAPDH as determined by qPCR, performed in technical triplicate in CCRF-CEM cells exposed to 1 μM DEX and 100 ng/mL IL-7 for the indicated duration. (C) MFI of IL-7Rα in CCRF-CEM cells treated with or without 1 μM DEX and/or 10 μg/mL CHX in technical triplicate for 24 hours. Inset shows representative histograms of IL-7Rα in CCRF-CEM cells treated with or without 1 μM DEX and/or 10 μg/mL CHX for 24 hours. (D) MFI of p-STAT5 in CCRF-CEM cells treated with or without 1 μM DEX for 24 hours in the absence of IL-7 followed by a 1-hour exposure to vehicle control or RUX prior to a 15-minute stimulation with 100 ng/mL IL-7 in technical triplicate. Significance is relative to the DEX-treated condition in the absence of IL-7 stimulation. (E) Relative luminescence of CCRF-CEM cells transfected with the STAT5 reporter construct and treated with or without 1 μM DEX, 100 ng/mL IL-7, and 500 nM RUX in technical triplicate for 36 hours prior to lysis and measurement of luciferase activity. (F) GSEA plots of STAT5 gene expression signatures comparing scramble control clones (n = 4) treated with 100 ng/mL IL-7 versus the combination of 1 μM DEX and 100 ng/mL IL-7 for 16 hours. **P < 0.01 and ****P < 0.0001, by 1-way ANOVA with Tukey’s method for multiple comparisons adjustment (B–E). With the exception of the RNA-Seq experiment, all data are representative of 3 independent experiments.