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 4

BCL-2 mediates IL-7–induced DEX resistance.

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BCL-2 mediates IL-7–induced DEX resistance. (A) Percentage of priming of...
(A) Percentage of priming of CCRF-CEM cells treated in the absence or presence of 1 μM DEX and/or 100 ng/mL IL-7 in technical triplicate for 16 hours followed by BH3 profiling with 0.5 μM ABT-199 for 90 minutes. (B) Viability of CCRF-CEM cells treated with DEX in the absence or presence of 25 ng/mL IL-7 and increasing concentrations of ABT-199 for 72 hours in technical triplicate. The no IL-7 (black line) and the 25 ng/mL IL-7 (red line) conditions were replotted from Figure 1C. (C) Heatmap of Bliss independence scores calculated as the average of technical triplicates for the combination of DEX and ABT-199 in the presence of 25 ng/mL IL-7. (D) MFI of BCL-2 protein expression assessed in technical triplicate in untransduced CCRF-CEM cells and CCRF-CEM cells transduced with a nontargeting shRNA control (shControl) or a BCL2-targeting shRNA (shBCL2-1-5). Statistical significance is relative to the untransduced cells. (E) Viability of untransduced or shRNA-transduced CCRF-CEM cells treated with DEX in the absence or presence of 25 ng/mL IL-7 in technical triplicate for 72 hours. (F) FPKM values for BCL2 transcript levels according to published RNA-Seq data from diagnostic samples from patients enrolled in the COG AALL0434 trial, stratified on the basis of day-29 bone marrow MRD. (G) Schematic of the proposed model for the mechanism by which DEX paradoxically induces steroid resistance in T-ALL cells in the presence of IL-7. In the presence of DEX (right), the GR induces an increase in IL-7R expression (i), leading to an increase in IL-7R at the cell surface (ii). This in turn leads to an increase in STAT5 transcriptional activity (iii) that ultimately results in the upregulation of BCL-2 (iv). GRE, glucocorticoid response element. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA with Tukey’s method for multiple comparisons adjustment (A, D, and F). All CCRF-CEM cell data are representative of 3 independent experiments.