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 6

T-ALLs reflecting early stages of T cell development demonstrate DEX resistance in the presence of IL-7.

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T-ALLs reflecting early stages of T cell development demonstrate DEX res...
(A) Heatmap depicting the clustering of 76 primary T-ALL samples by the expression of genes that are upregulated in early developing thymocytes relative to later developing thymocytes. (B) MFI of cell-surface IL-7Rα in 15 early and 12 late T-ALL PDX samples following exposure to 1 μM DEX for 24 hours in technical triplicate. (C) Viability relative to vehicle control of 15 early and 12 late T-ALL PDX samples treated with 1 μM DEX in the absence or presence of 25 ng/mL IL-7 for 48 hours in technical triplicate. (D) MFI of BCL-2 protein expression in 10 early T-ALL PDX samples following exposure to 100 ng/mL IL-7 with or without 1 μM DEX and/or 500 nM RUX for 16 hours in technical triplicate. Some samples were not analyzed because of limited cell numbers. (E) Viability relative to vehicle control of 15 early T-ALL samples exposed to 25 ng/mL IL-7 with or without 1 μM DEX and/or 500 nM RUX or 1 μM ABT-199 for 48 hours in technical triplicate. (F) Kaplan-Meier survival analysis of mice transplanted with early T-ALL T24 and treated with vehicle control (n = 5), DEX (n = 5), RUX (n = 5), or a combination of DEX and RUX (n = 5). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by paired t test (B and C), 1-way ANOVA with Tukey’s method for multiple comparisons adjustment (D and E), or a log-rank test (F).