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Nat Genet. 2015 Jun;47(6):607-14. doi: 10.1038/ng.3283. Epub 2015 May 4.

NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells.

Author information

  • 11] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 2HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
  • 3Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 4Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 5High-Performance Computing Facility, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 6Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 7Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 8Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 91] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [3] Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 101] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 11Division of Pediatric Oncology-Hematology, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands.
  • 121] Division of Pediatric Oncology-Hematology, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands. [2] Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
  • 131] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 14Centre for Rare Diseases and Personalized Medicine, University of Birmingham, Birmingham, UK.
  • 15New York University Cancer Institute, New York University Langone Medical Center, New York, New York, USA.

Abstract

Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and resistance to glucocorticoids in leukemia cells confers poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the prednisolone sensitivity of primary leukemia cells from 444 patients newly diagnosed with ALL and found significantly higher expression of CASP1 (encoding caspase 1) and its activator NLRP3 in glucocorticoid-resistant leukemia cells, resulting from significantly lower somatic methylation of the CASP1 and NLRP3 promoters. Overexpression of CASP1 resulted in cleavage of the glucocorticoid receptor, diminished the glucocorticoid-induced transcriptional response and increased glucocorticoid resistance. Knockdown or inhibition of CASP1 significantly increased glucocorticoid receptor levels and mitigated glucocorticoid resistance in CASP1-overexpressing ALL. Our findings establish a new mechanism by which the NLRP3-CASP1 inflammasome modulates cellular levels of the glucocorticoid receptor and diminishes cell sensitivity to glucocorticoids. The broad impact on the glucocorticoid transcriptional response suggests that this mechanism could also modify glucocorticoid effects in other diseases.

PMID:
25938942
[PubMed - indexed for MEDLINE]
PMCID:
PMC4449308
Free PMC Article
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