Loss of glucocorticoid receptor expression mediates in vivo dexamethasone resistance in T-cell acute lymphoblastic leukemia
| Autor: | Qing Li, Jon C. Aster, Hannah Yan, Joy Nakitandwe, Kevin Shannon, Robert P. Hasserjian, Alessandro Scacchetti, Jasmine C. Wong, Olga K. Weinberg, James R. Downing, Monique Dail, Anica M. Wandler, Jeffrey W. Craig, Jinghui Zhang, Lauren K. Meyer, Benjamin J. Huang, Philip Jonsson, Kathryn Hayes, Deepak Sampath, Gabriela C. Monsalve, Keith R. Yamamoto, Scott C. Kogan, Barry S. Taylor |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Cancer Research Drug Resistance Inbred C57BL Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Dexamethasone Mice 0302 clinical medicine Glucocorticoid receptor Glucocorticoid Genome editing Recurrence Receptors Cancer Pediatric Sulfonamides Kinase Hematology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis hormones hormone substitutes and hormone antagonists medicine.drug Biotechnology Indazoles Pediatric Cancer Childhood Leukemia T cell Clinical Sciences Oncology and Carcinogenesis Immunology Biology Article 03 medical and health sciences Receptors Glucocorticoid Rare Diseases In vivo medicine Genetics Animals Humans Gene Mice Inbred C57BL 030104 developmental biology Drug Resistance Neoplasm Mutation Cancer research Neoplasm |
| Zdroj: | Leukemia, vol 34, iss 8 Leukemia |
| Popis: | 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 low glucocorticoid receptor (GR) protein expression. A similar proportion of relapsed human T-ALLs also exhibited markedly reduced GR protein levels. De novo or pre-existing 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. |
| Databáze: | OpenAIRE |
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