- 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
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.