1. Loss of glucocorticoid receptor expression mediates in vivo dexamethasone resistance in T-cell acute lymphoblastic leukemia
- 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, and Shannon, Kevin
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Cancer ,Hematology ,Pediatric Cancer ,Rare Diseases ,Genetics ,Childhood Leukemia ,Pediatric ,Orphan Drug ,Animals ,Dexamethasone ,Drug Resistance ,Neoplasm ,Humans ,Indazoles ,Male ,Mice ,Mice ,Inbred C57BL ,Mutation ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,Receptors ,Glucocorticoid ,Recurrence ,Sulfonamides ,Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cardiovascular medicine and haematology ,Clinical sciences ,Oncology and carcinogenesis - 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.
- Published
- 2020