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Loss of glucocorticoid receptor expression mediates in vivo dexamethasone resistance in T-cell acute lymphoblastic leukemia
- Source :
- Leukemia, vol 34, iss 8, Leukemia
- Publication Year :
- 2020
- Publisher :
- eScholarship, University of California, 2020.
-
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 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.
- Subjects :
- 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
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Leukemia, vol 34, iss 8, Leukemia
- Accession number :
- edsair.doi.dedup.....4aeabda681f2400375386b07498df6cf