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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.

Author information

1
Department of Pediatrics, UCSF, San Francisco, California, USA.
2
Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
3
Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
4
Cancer Genomics and Bioinformatics Laboratory, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
5
Department of Epidemiology and Biostatistics, UCSF, San Francisco, California, USA.
6
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.
7
Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, Texas, USA.

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.

KEYWORDS:

Leukemias; Oncology; Signal transduction; T cells

PMID:
31687977
PMCID:
PMC6994137
[Available on 2020-05-03]
DOI:
10.1172/JCI130189
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