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J Clin Invest. 2020 Feb 3;130(2):863-876. doi: 10.1172/JCI130189.

Glucocorticoids paradoxically facilitate steroid resistance in T cell acute lymphoblastic leukemias and thymocytes.

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Department of Pediatrics, UCSF, San Francisco, California, USA.
Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Cancer Genomics and Bioinformatics Laboratory, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Department of Epidemiology and Biostatistics, UCSF, San Francisco, California, USA.
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.
Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, Texas, USA.


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.


Leukemias; Oncology; Signal transduction; T cells

[Available on 2020-05-03]
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