Loss of Glucocorticoid Receptor Expression Mediates in Vivo Dexamethasone Resistance in T-cell Acute Lymphoblastic Leukemia

Details

• Alternative Title:
  Leukemia
• Personal Author:
  Wandler, Anica M. ; Huang, Benjamin J. ; Craig, Jeffrey W. ; Hayes, Kathryn ; Yan, Hannah ; Meyer, Lauren K. ; Scacchetti, Alessandro ; Monsalve, Gabriela ; Dail, Monique ; Li, Qing ; Wong, Jasmine C. ; Weinberg, Olga ; Hasserjian, Robert P. ; Kogan, Scott C. ; Jonsson, Philip ; Yamamoto, Keith ; Sampath, Deepak ; Nakitandwe, Joy ; Downing, James R. ; Zhang, Jinghui ; Aster, Jon C. ; Taylor, Barry S. ; Shannon, Kevin
• Description:
  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.
• Subjects:
  Article
• Source:
  Leukemia. 34(8):2025-2037
• Pubmed ID:
  32066867
• Pubmed Central ID:
  PMC7440098
• Document Type:
  Journal Article
• Funding:
  U54 OD020355/OD/NIH HHS/United States ; P30 CA082103/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R37 CA072614/CA/NCI NIH HHS/United States ; R01 CA180037/CA/NCI NIH HHS/United States ; T32 CA128583/CA/NCI NIH HHS/United States ; R01 CA204749/CA/NCI NIH HHS/United States ; Young Investigator Grant/Alex's Lemonade Stand Foundation for Childhood Cancer (Alex's Lemonade Stand Foundation)/ ; U54 OD020355/CD/ODCDC CDC HHS/United States ; R50 CA211452/CA/NCI NIH HHS/United States ; PF-14-070-01-TBG/American Cancer Society (American Cancer Society, Inc.)/ ; R37 CA72614/Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R01 CA072614/CA/NCI NIH HHS/United States ; RP 10-078-01-TBE/American Cancer Society (American Cancer Society, Inc.)/ ; RSG-15-067-01-TBG/American Cancer Society (American Cancer Society, Inc.)/ ; Research Grant/St. Baldrick's Foundation (St. Baldrick's Foundation, Inc)/
• Volume:
  34
• Issue:
  8
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:2e38e6e203bf0dc5954d320ae462824e903908b72a1afebc431b0ae4993808cc
• Download URL:
  https://stacks.cdc.gov/view/cdc/92338/cdc_92338_DS1.pdf
• File Type:
  [PDF - 1.57 MB ]