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

Anica M. Wandler, Benjamin J. Huang, Jeffrey W. Craig, Kathryn Hayes, Hannah Yan, Lauren K. Meyer, Alessandro Scacchetti, Gabriela Monsalve, Monique Dail, Qing Li, Jasmine C. Wong, Olga Weinberg, Robert P. Hasserjian, Scott C. Kogan, Philip Jonsson, Keith Yamamoto, Deepak Sampath, Joy Nakitandwe, James R. Downing, Jinghui ZhangJon C. Aster, Barry S. Taylor, Kevin Shannon

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2025-2037
Number of pages13
JournalLeukemia
Volume34
Issue number8
DOIs
StatePublished - Aug 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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