Loss of glucocorticoid receptor expression mediates in vivo dexamethasone resistance in T-cell acute lymphoblastic leukemia

Leukemia. 2020 Aug;34(8):2025-2037. doi: 10.1038/s41375-020-0748-6. Epub 2020 Feb 17.


Despite decades of clinical use, mechanisms of glucocorticoid resistance are poorly understood. We treated primary murine T lineage acute lymphoblastic leukemias (T-ALLs) with the glucocorticoid dexamethasone (DEX) alone and in combination with the pan-PI3 kinase inhibitor GDC-0941 and observed a robust response to DEX that was modestly enhanced by GDC-0941. Continuous in vivo treatment invariably resulted in outgrowth of drug-resistant clones, ~30% of which showed markedly reduced glucocorticoid receptor (GR) protein expression. A similar proportion of relapsed human T-ALLs also exhibited low GR protein levels. De novo or preexisting mutations in the gene encoding GR (Nr3c1) occurred in relapsed clones derived from multiple independent parental leukemias. CRISPR/Cas9 gene editing confirmed that loss of GR expression confers DEX resistance. Exposing drug-sensitive T-ALLs to DEX in vivo altered transcript levels of multiple genes, and this response was attenuated in relapsed T-ALLs. These data implicate reduced GR protein expression as a frequent cause of glucocorticoid resistance in T-ALL.

Publication types

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

MeSH terms

  • Animals
  • Dexamethasone / administration & dosage
  • Dexamethasone / therapeutic use*
  • Drug Resistance, Neoplasm
  • Humans
  • Indazoles / administration & dosage
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Receptors, Glucocorticoid / analysis*
  • Receptors, Glucocorticoid / genetics
  • Recurrence
  • Sulfonamides / administration & dosage


  • 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
  • Indazoles
  • NR3C1 protein, mouse
  • Receptors, Glucocorticoid
  • Sulfonamides
  • Dexamethasone