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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Resistance, Neoplasm* / immunology
  • Glucocorticoids / pharmacology*
  • Humans
  • Interleukin-7 / immunology
  • Interleukin-7 Receptor alpha Subunit / immunology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / immunology
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / pathology
  • Proto-Oncogene Proteins c-bcl-2 / immunology
  • STAT5 Transcription Factor / immunology
  • Signal Transduction* / drug effects
  • Signal Transduction* / immunology
  • Thymocytes* / immunology
  • Thymocytes* / pathology
  • Xenograft Model Antitumor Assays


  • BCL2 protein, human
  • Glucocorticoids
  • IL7 protein, human
  • IL7R protein, human
  • Interleukin-7
  • Interleukin-7 Receptor alpha Subunit
  • Proto-Oncogene Proteins c-bcl-2
  • STAT5 Transcription Factor