Loss of glucocorticoid receptor expression mediates in vivo dexamethasone resistance in T-cell acute lymphoblastic leukemia Journal Article
| Authors: | Wandler, A. M.; Huang, B. J.; Craig, J. W.; Hayes, K.; Yan, H.; Meyer, L. K.; Scacchetti, A.; Monsalve, G.; Dail, M.; Li, Q.; Wong, J. C.; Weinberg, O.; Hasserjian, R. P.; Kogan, S. C.; Jonsson, P.; Yamamoto, K.; Sampath, D.; Nakitandwe, J.; Downing, J. R.; Zhang, J.; Aster, J. C.; Taylor, B. S.; Shannon, K. |
| Article Title: | Loss of glucocorticoid receptor expression mediates in vivo dexamethasone resistance in T-cell acute lymphoblastic leukemia |
| 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. © 2020, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | protein kinase b; s6 kinase; adult; cancer survival; child; controlled study; human tissue; protein expression; treatment response; somatic mutation; drug efficacy; drug potentiation; nonhuman; treatment duration; validation process; mouse; animal experiment; animal model; gene frequency; dexamethasone; in vivo study; in vitro study; acute lymphoblastic leukemia; enzyme phosphorylation; messenger rna; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; gene loss; ras protein; transcriptome; protein cleavage; complementary dna; notch1 receptor; rna sequence; glucocorticoid receptor; rna analysis; indel mutation; genetic difference; pictilisib; sanger sequencing; human; male; female; priority journal; article; median survival time; whole exome sequencing; gene editing; crispr-cas9 system; nr3c1 gene |
| Journal Title: | Leukemia |
| Volume: | 34 |
| Issue: | 8 |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2020-08-01 |
| Start Page: | 2025 |
| End Page: | 2037 |
| Language: | English |
| DOI: | 10.1038/s41375-020-0748-6 |
| PUBMED: | 32066867 |
| PROVIDER: | scopus |
| PMCID: | PMC7440098 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 September 2020 -- Source: Scopus |
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