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- Title
Glucocorticoids paradoxically facilitate steroid resistance in T cell acute lymphoblastic leukemias and thymocytes.
- Authors
Meyer, Lauren K.; Huang, Benjamin J.; Delgado-Martin, Cristina; Roy, Ritu P.; Hechmer, Aaron; Wandler, Anica M.; Vincent, Tiffaney L.; Fortina, Paolo; Olshen, Adam B.; Wood, Brent L.; Horton, Terzah M.; Shannon, Kevin M.; Teachey, David T.; Hermiston, Michelle L.
- 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.
- Subjects
LYMPHOBLASTIC leukemia; T cells; ACUTE leukemia; CELL physiology; GLUCOCORTICOIDS; PROTEINS; INTERLEUKINS; RESEARCH; ANIMAL experimentation; RESEARCH methodology; CELL receptors; EVALUATION research; MEDICAL cooperation; CELLULAR signal transduction; COMPARATIVE studies; CELLS; DRUG resistance in cancer cells; MICE; CARRIER proteins
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 2, p863
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI130189