Loss of glucocorticoid receptor expression mediates in vivo dexamethasone resistance in T-cell acute lymphoblastic leukemia.

Autor: Wandler AM; Department of Pediatrics, University of California, San Francisco, CA, USA., Huang BJ; Department of Pediatrics, University of California, San Francisco, CA, USA., Craig JW; Department of Pathology, Brigham & Women's Hospital, Boston, MA, USA., Hayes K; Department of Pediatrics, University of California, San Francisco, CA, USA., Yan H; Department of Pediatrics, University of California, San Francisco, CA, USA., Meyer LK; Department of Pediatrics, University of California, San Francisco, CA, USA., Scacchetti A; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA., Monsalve G; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA., Dail M; Department of Translational Oncology, Genentech Inc., South San Francisco, CA, USA., Li Q; Department of Medicine, University of Michigan, Ann Arbor, MI, USA., Wong JC; Department of Pediatrics, University of California, San Francisco, CA, USA., Weinberg O; Department of Pathology, Boston Children's Hospital, Boston, MA, USA., Hasserjian RP; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA., Kogan SC; Department of Laboratory Medicine, University of California, San Francisco, CA, USA., Jonsson P; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Yamamoto K; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA., Sampath D; Department of Translational Oncology, Genentech Inc., South San Francisco, CA, USA., Nakitandwe J; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA., Downing JR; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA., Zhang J; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Aster JC; Department of Pathology, Brigham & Women's Hospital, Boston, MA, USA., Taylor BS; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Shannon K; Department of Pediatrics, University of California, San Francisco, CA, USA. kevin.shannon@ucsf.edu.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2020 Aug; Vol. 34 (8), pp. 2025-2037. Date of Electronic Publication: 2020 Feb 17.
DOI: 10.1038/s41375-020-0748-6
Abstrakt: 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.
Databáze: MEDLINE